6-, 7-, or 8-substituted quinazolinone derivatives and compositions comprising and methods of using the same

ABSTRACT

Provided are quinazolinone compounds, and pharmaceutically acceptable salts, solvates, clathrates, stereoisomers, and prodrugs thereof. Methods of use, and pharmaceutical compositions of these compounds are disclosed.

This application claims priority to U.S. provisional application No.60/995,676, filed Sep. 26, 2007, the entirety of which is incorporatedherein by reference.

1. FIELD OF THE INVENTION

Provided herein are quinzolinone derivatives. Pharmaceuticalcompositions comprising the compounds and methods for treating,preventing and managing various disorders are also disclosed.

2. BACKGROUND OF THE INVENTION 2.1 PATHOBIOLOGY OF CANCER AND OTHERDISEASES

Cancer is characterized primarily by an increase in the number ofabnormal cells derived from a given normal tissue, invasion of adjacenttissues by these abnormal cells, or lymphatic or blood-borne spread ofmalignant cells to regional lymph nodes and to distant sites(metastasis). Clinical data and molecular biologic studies indicate thatcancer is a multistep process that begins with minor preneoplasticchanges, which may under certain conditions progress to neoplasia. Theneoplastic lesion may evolve clonally and develop an increasing capacityfor invasion, growth, metastasis, and heterogeneity, especially underconditions in which the neoplastic cells escape the host's immunesurveillance. Roitt, I., Brostoff, J and Kale, D., Immunology,17.1-17.12 (3rd ed. Mosby, St. Louis, Mo., 1993).

There is an enormous variety of cancers which are described in detail inthe medical literature. Examples includes cancer of the lung, colon,rectum, prostate, breast, brain, and intestine. The incidence of cancercontinues to climb as the general population ages, as new cancersdevelop, and as susceptible populations (e.g., people infected with AIDSor excessively exposed to sunlight) grow. However, options for thetreatment of cancer are limited. For example, in the case of bloodcancers (e.g., multiple myeloma), few treatment options are available,especially when conventional chemotherapy fails and bone-marrowtransplantation is not an option. A tremendous demand therefore existsfor new methods and compositions that can be used to treat patients withcancer.

Many types of cancers are associated with new blood vessel formation, aprocess known as angiogenesis. Several of the mechanisms involved intumor-induced angiogenesis have been elucidated. The most direct ofthese mechanisms is the secretion by the tumor cells of cytokines withangiogenic properties. Examples of these cytokines include acidic andbasic fibroblastic growth factor (a,b-FGF), angiogenin, vascularendothelial growth factor (VEGF), and TNF-α. Alternatively, tumor cellscan release angiogenic peptides through the production of proteases andthe subsequent breakdown of the extracellular matrix where somecytokines are stored (e.g., b-FGF). Angiogenesis can also be inducedindirectly through the recruitment of inflammatory cells (particularlymacrophages) and their subsequent release of angiogenic cytokines (e.g.,INF-α, b-FGF).

A variety of other diseases and disorders are also associated with, orcharacterized by, undesired angiogenesis. For example, enhanced orunregulated angiogenesis has been implicated in a number of diseases andmedical conditions including, but not limited to, ocular neovasculardiseases, choroidal neovascular diseases, retina neovascular diseases,rubeosis (neovascularization of the angle), viral diseases, geneticdiseases, inflammatory diseases, allergic diseases, and autoimmunediseases. Examples of such diseases and conditions include, but are notlimited to: diabetic retinopathy; retinopathy of prematurity; cornealgraft rejection; neovascular glaucoma; retrolental fibroplasia;arthritis; and proliferative vitreoretinopathy.

Accordingly, compounds that can control angiogenesis or inhibit theproduction of certain cytokines, including TNFα, may be useful in thetreatment and prevention of various diseases and conditions.

2.2 METHODS OF TREATING CANCER

Current cancer therapy may involve surgery, chemotherapy, hormonaltherapy and/or radiation treatment to eradicate neoplastic cells in apatient (see, e.g., Stockdale, 1998, Medicine, vol. 3, Rubenstein andFederman, eds., Chapter 12, Section IV). Recently, cancer therapy couldalso involve biological therapy or immunotherapy. All of theseapproaches pose significant drawbacks for the patient. Surgery, forexample, may be contraindicated due to the health of a patient or may beunacceptable to the patient. Additionally, surgery may not completelyremove neoplastic tissue. Radiation therapy is only effective when theneoplastic tissue exhibits a higher sensitivity to radiation than normaltissue. Radiation therapy can also often elicit serious side effects.Hormonal therapy is rarely given as a single agent. Although hormonaltherapy can be effective, it is often used to prevent or delayrecurrence of cancer after other treatments have removed the majority ofcancer cells. Biological therapies and immunotherapies are limited innumber and may produce side effects such as rashes or swellings,flu-like symptoms, including fever, chills and fatigue, digestive tractproblems or allergic reactions.

With respect to chemotherapy, there are a variety of chemotherapeuticagents available for treatment of cancer. A majority of cancerchemotherapeutics act by inhibiting DNA synthesis, either directly, orindirectly by inhibiting the biosynthesis of deoxyribonucleotidetriphosphate precursors, to prevent DNA replication and concomitant celldivision. Gilman et al., Goodman and Gilman's: The Pharmacological Basisof Therapeutics, Tenth Ed. (McGraw Hill, New York).

Despite availability of a variety of chemotherapeutic agents,chemotherapy has many drawbacks. Stockdale, Medicine, vol. 3, Rubensteinand Federman, eds., ch. 12, sect. 10, 1998. Almost all chemotherapeuticagents are toxic, and chemotherapy causes significant, and oftendangerous side effects including severe nausea, bone marrow depression,and immunosuppression. Additionally, even with administration ofcombinations of chemotherapeutic agents, many tumor cells are resistantor develop resistance to the chemotherapeutic agents. In fact, thosecells resistant to the particular chemotherapeutic agents used in thetreatment protocol often prove to be resistant to other drugs, even ifthose agents act by different mechanism from those of the drugs used inthe specific treatment. This phenomenon is referred to as pleiotropicdrug or multidrug resistance. Because of the drug resistance, manycancers prove or become refractory to standard chemotherapeutictreatment protocols.

Other diseases or conditions associated with, or characterized by,undesired angiogenesis are also difficult to treat. However, somecompounds such as protamine, hepain and steroids have been proposed tobe useful in the treatment of certain specific diseases. Taylor et al.,Nature 297:307 (1982); Folkman et al., Science 221:719 (1983); and U.S.Pat. Nos. 5,001,116 and 4,994,443.

Still, there is a significant need for effective methods of treating,preventing and managing cancer and other diseases and conditions,including for diseases that are refractory to standard treatments, suchas surgery, radiation therapy, chemotherapy and hormonal therapy, whilereducing or avoiding the toxicities and/or side effects associated withthe conventional therapies.

3. SUMMARY OF THE INVENTION

Provided herein are quinazolinone compounds, and pharmaceuticallyacceptable salts, solvates (e.g., hydrates), prodrugs, clathrates, orstereoisomers thereof.

Also provided are methods of treating and managing various diseases ordisorders. The methods comprise administering to a patient in need ofsuch treatment or management, or having such a disease or disorder, atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable salt, solvate, prodrug, clathrate, orstereoisomer thereof.

Also provided herein are methods of preventing various diseases anddisorders, which comprise administering to a patient in need of suchprevention, or at a risk of such a disease or disorder, aprophylactically effective amount of a compound provided herein, or apharmaceutically acceptable salt, solvate, prodrug, clathrate, orstereoisomer thereof.

Also provided herein are pharmaceutical compositions, single unit dosageforms, dosing regimens and kits which comprise a compound providedherein, or a pharmaceutically acceptable salt, solvate, prodrug,clathrate, or stereoisomer thereof.

4. DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, provided are quinazolinone compounds, andpharmaceutically acceptable salts, solvates, prodrugs, clathrate, andstereoisomers thereof.

In another embodiment, provided are methods of treating, managing, andpreventing various diseases and disorders, which comprises administeringto a patient a therapeutically or prophylactically effective amount of acompound provided herein, or a pharmaceutically acceptable salt,solvate, prodrug, clathrate, or stereoisomer thereof. Examples ofdiseases and disorders are described herein.

In other embodiments, a compound provided herein, or a pharmaceuticallyacceptable salt, solvate, prodrug, clathrate, or stereoisomer thereof,is administered in combination with another drug (“second active agent”)or treatment. Second active agents include small molecules and largemolecules (e.g., proteins and antibodies), examples of which areprovided herein, as well as stem cells. Methods, or therapies, that canbe used in combination with the administration of compounds providedherein include, but are not limited to, surgery, blood transfusions,immunotherapy, biological therapy, radiation therapy, and other non-drugbased therapies presently used to treat, prevent or manage variousdisorders described herein.

Also provided are pharmaceutical compositions (e.g., single unit dosageforms) that can be used in the methods provided herein. In oneembodiment, pharmaceutical compositions comprise a compound providedherein, or a pharmaceutically acceptable salt, solvate, prodrug,clathrate, or stereoisomer thereof, and optionally a second activeagent.

4.1 COMPOUNDS

In one embodiment, the compounds provided herein for use in thepharmaceutical compositions and methods have the formula (I):

and pharmaceutically acceptable salts, solvates, and stereoisomersthereof, wherein:

-   R¹ is hydrogen;-   each of R², R³, and R⁴ is independently: hydrogen; halo;    —(CH₂)_(n)OH; (C₁-C₆)alkyl, optionally substituted with one or more    halo; (C₁-C₆)alkoxy, optionally substituted with one or more halo;    or    -   —(CH₂)NHR^(a), wherein R^(a) is:        -   hydrogen;        -   (C₁-C₆)alkyl, optionally substituted with one or more halo;        -   —(CH₂)_(n)-(6 to 10 membered aryl);        -   —C(O)—(CH₂)_(n)-(6 to 10 membered aryl) or            —C(O)—(CH₂)_(n)-(6 to 10 membered heteroaryl), wherein the            aryl or heteroaryl is optionally substituted with one or            more of: halo; —SCF₃; (C₁-C₆)alkyl, said alkyl itself            optionally substituted with one or more halo; or            (C₁-C₆)alkoxy, said alkoxy itself optionally substituted            with one or more halo;        -   —C(O)—(C₁-C₈)alkyl, wherein the alkyl is optionally            substituted with one or more halo;        -   —C(O)—(CH₂)_(n)—(C₃-C₁₀-cycloalkyl);        -   —C(O)—(CH₂)_(n)—NR^(b)R^(c), wherein R^(b) and R^(c) are            each independently:            -   hydrogen;            -   (C₁-C₆)alkyl, optionally substituted with one or more                halo;            -   (C₁-C₆)alkoxy, optionally substituted with one or more                halo; or            -   6 to 10 membered aryl, optionally substituted with one                or more of: halo; (C₁-C₆)alkyl, itself optionally                substituted with one or more halo; or (C₁-C₆)alkoxy,                itself optionally substituted with one or more halo;        -   —C(O)—(CH₂)_(n)—O—(C₁-C₆)alkyl; or        -   —C(O)—(CH₂)_(n)—O—(CH₂)_(n)-(6 to 10 membered aryl); or-   two of R¹-R⁴ together can form a 5 or 6 membered ring, optionally    substituted with one or more of halo; (C₁-C₆)alkyl, optionally    substituted with one or more halo; and (C₁-C₆)alkoxy, optionally    substituted with one or more halo;-   R⁵ is: hydrogen; —(CH₂)_(n)OH; phenyl; —O—(C₁-C₆)alkyl; or    (C₁-C₆)alkyl, optionally substituted with one or more halo;-   R⁶ is: hydrogen; or (C₁-C₆)alkyl, optionally substituted with one or    more halo; and-   n is 0, 1, or 2.

In another embodiment, provided herein are compounds of formula (II):

and pharmaceutically acceptable salts, solvates, and stereoisomersthereof, wherein:

-   R⁷ is: hydrogen; halo; —(CH₂)_(n)OH; (C₁-C₆)alkyl, optionally    substituted with one or more halo; (C₁-C₆)alkoxy, optionally    substituted with one or more halo; or    -   —(CH₂)_(n)NHR^(d), wherein R^(d) is:        -   hydrogen;        -   (C₁-C₆)alkyl, optionally substituted with one or more halo;        -   —(CH₂)_(n)-(6 to 10 membered aryl);        -   —C(O)—(CH₂)_(n)-(6 to 10 membered aryl) or —C(O)—(CH₂)_(n)(6            to 10 membered heteroaryl), wherein the aryl or heteroaryl            is optionally substituted with one or more of: halo; —SCF₃;            (C₁-C₆)alkyl, itself optionally substituted with one or more            halo; or (C₁-C₈)alkoxy, itself optionally substituted with            one or more halo;        -   —C(O)—(C₁-C₈)alkyl, wherein the alkyl is optionally            substituted with one or more halo;        -   —C(O)—(CH₂)_(n)—(C₁-C₁₀-cycloalkyl);        -   —C(O)—(CH₂)_(n)—NR^(e)R^(f), wherein R^(e) and R^(f) are            each independently:            -   hydrogen;            -   (C₁-C₆)alkyl, optionally substituted with one or more                halo;            -   (C₁-C₆)alkoxy, optionally substituted with one or more                halo; or            -   6 to 10 membered aryl, optionally substituted with one                or more of: halo; (C₁-C₆)alkyl, itself optionally                substituted with one or more halo; or (C₁-C₆)alkoxy,                itself optionally substituted with one or more halo;        -   —C(O)—(CH₂)_(n)—O—(C₁-C₆)alkyl; or        -   —C(O)—(CH₂)_(n)—O—(CH₂)_(n)-(6 to 10 membered aryl);-   R⁸ is: hydrogen; —(CH₂)_(n)OH; phenyl; —O—(C₁-C₆)alkyl; or    (C₁-C₆)alkyl, optionally substituted with one or more halo;-   R⁹ is: hydrogen; or (C₁-C₆)alkyl, optionally substituted with one or    more halo; and-   n is 0, 1, or 2.

In another embodiment, provided herein are compounds of formula (III):

and pharmaceutically acceptable salts, solvates, and stereoisomersthereof, wherein:

-   R¹⁰ is: hydrogen; halo; —(CH₂)_(n)OH; (C₁-C₆)alkyl, optionally    substituted with one or more halo; or (C₁-C₆)alkoxy, optionally    substituted with one or more halo;-   R¹¹ is: hydrogen; —(CH₂)_(n)OH: phenyl; —O—(C₁-C₆)alkyl; or    (C₁-C₆)alkyl, optionally substituted with one or more halo;-   R¹² is: hydrogen; or (C₁-C₆)alkyl, optionally substituted with one    or more halo; and-   n is 0, 1, or 2.

In one embodiment, R¹⁰ is hydrogen. In another embodiment, R¹⁰ is halo.In another embodiment, R¹⁰ is (C₁-C₆)alkyl, optionally substituted withone or more halo. In another embodiment, R₁₀ is —(CH₂)_(n)OH orhydroxyl. In another embodiment, R¹⁰ is (C₁-C₆)alkoxy, optionallysubstituted with one or more halo.

In one embodiment, R¹¹ is hydrogen. In another emdodiment, R¹¹ is—(CH₂)_(n)OH or hydroxyl. In another emdodiment, R¹¹ is phenyl. Inanother emdodiment, R¹¹ is —O—(C₁-C₆)alkyl, optionally substituted withone or more halo. In another emdodiment, R¹¹ is (C₁-C₆)alkyl, optionallysubstituted with one or more halo.

In one embodiment, R¹² is hydrogen. In another embodiment, R¹² is(C₁-C₆)alkyl, optionally substituted with one or more halo.

In one embodiment, n is 0. In another embodiment, n is 1. In anotherembodiment, n is 2.

Compounds provided herein encompass any of the combinations of R¹⁰, R¹¹,R¹² and n described above.

In one specific embodiment, R¹⁰ is halo. In another embodiment, R¹⁰ ishydroxyl. In another embodiment, R¹⁰ is methyl.

In another specific embodiment, R¹¹ is hydrogen. In another embodiment,R¹¹ is methyl.

In another specific embodiment, R¹² is hydrogen. In another embodiment,R¹² is methyl.

Specific compounds include, but are not limited to:

In another embodiment, provided herein are compounds of formula (IV):

and pharmaceutically acceptable salts, solvates, and stereoisomersthereof, wherein:

-   R^(g) is:    -   hydrogen;    -   (C₁-C₆)alkyl, optionally substituted with one or more halo;    -   —(CH₂)_(n)-(6 to 10 membered aryl);    -   —C(O)—(CH₂)_(n)-(6 to 10 membered aryl) or —C(O)—(CH₂)_(n)-(6 to        10 membered heteroaryl), wherein the aryl or heteroaryl is        optionally substituted with one or more of: halo; —SCF₃;        (C₁-C₆)alkyl, itself optionally substituted with one or more        halo; or (C₁-C₆)alkoxy, itself optionally substituted with one        or more halo;    -   —C(O)—(C₁-C₈)alkyl, wherein the alkyl is optionally substituted        with one or more halo;    -   —C(O)—(CH₂)_(n)—(C₃-C₁₀-cycloalkyl);    -   —C(O)—(CH₂)_(n)—NR^(h)R^(i), wherein R^(h) and R^(i) are each        independently:        -   hydrogen;        -   (C₁-C₆)alkyl, optionally substituted with one or more halo;        -   (C₁-C₆)alkoxy, optionally substituted with one or more halo;            or        -   6 to 10 membered aryl, optionally substituted with one or            more of: halo; (C₁-C₆)alkyl, itself optionally substituted            with one or more halo; or (C₁-C₆)alkoxy, itself optionally            substituted with one or more halo;    -   —C(O)—(CH₂)_(n)—O—(C₁-C₆)alkyl; or    -   —C(O)—(CH₂)_(n)—O—(CH₂)_(n)-(6 to 10 membered aryl);-   R¹³ is: hydrogen; —(CH₂)_(n)OH; phenyl; —O—(C₁-C₆)alkyl; or    (C₁-C₆)alkyl, optionally substituted with one or more halo;-   R¹⁴ is: hydrogen; or (C₁-C₆)alkyl, optionally substituted with one    or more halo; and-   n is 0, 1, or 2.

In one embodiment, R^(g) is hydrogen. In abother embodiment, R^(g) is(C₁-C₆)alkyl, optionally substituted with one or more halo. In abotherembodiment, R^(g) is —(CH₂)_(n)-(6 to 10 membered aryl). In abotherembodiment, R^(b) is —C(O)—(CH₂)_(n)-(6 to 10 membered aryl) or—C(O)—(CH₂)_(n)-(6 to 10 membered heteroaryl), wherein the aryl orheteroaryl is optionally substituted as described above. In abotherembodiment, R^(g) is —C(O)—(C₁-C₈)alkyl, wherein the alkyl is optionallysubstituted with one or more halo. In abother embodiment, R^(g) is—C(O)—(CH₂)_(n)—(C₃-C₁₀-cycloalkyl). In abother embodiment, R^(g) is—C(O)—(CH₂)_(n)—NHR^(h)R^(i), wherein R^(h) and R^(i) are as describedabove. In abother embodiment. R^(g) is —C(O)—(CH₂)_(n)—O—(C₁-C₆)alkyl.In abother embodiment, R^(g) is —C(O)—(CH₂)_(n)—O—(CH₂)_(n)-(6 to 10membered aryl).

In one embodiment, R¹³ is hydrogen. In another emdodiment, R¹³ is—(CH₂)_(n)OH or hydroxyl. In another emdodiment, R¹³ is phenyl. Inanother emdodiment, R¹³ is —O—(C₁-C₆)alkyl, optionally substituted withone or more halo. In another emdodiment, R¹³ is (C₁-C₆)alkyl, optionallysubstituted with one or more halo.

In one embodiment, R¹⁴ is hydrogen. In another embodiment, R¹⁴ is(C₁-C₆)alkyl, optionally substituted with one or more halo.

In one embodiment, n is 0. In another embodiment, n is 1. In anotherembodiment, n is 2.

Compounds provided herein encompass any of the combinations of R^(g),R¹³, R¹⁴ and n described above.

In one specific embodiment, R^(g) is hydrogen, and n is 0 or 1. Inanother embodiment, R^(g) is —C(O)—(C₁-C₆)alkyl. In another embodiment,R^(g) is —C(O)-phenyl, optionally substituted with one or more methyl,halo, and/or (C₁-C₆)alkoxy.

In another specific embodiment, R¹³ is methyl. In another embodiment,R¹⁴ is hydrogen.

Specific compounds include, but are not limited to:

In another embodiment, provided herein are compounds of formula (V):

and pharmaceutically acceptable salts, solvates, and stereoisomersthereof, wherein:

-   R¹⁵ is: hydrogen; halo; —(CH₂)_(n)OH; (C₁-C₆)alkyl, optionally    substituted with one or more halo; (C₁-C₆)alkoxy, optionally    substituted with one or more halo; or    -   —(CH₂)_(n)NHR^(j), wherein R^(j) is:        -   hydrogen;        -   (C₁-C₆)alkyl, optionally substituted with one or more halo;        -   —(CH₂)_(n)-(6 to 10 membered aryl);        -   —C(O)—(CH₂)_(n)-(6 to 10 membered aryl) or            —C(O)—(CH₂)_(n)-(6 to 10 membered heteroaryl), wherein the            aryl or heteroaryl is optionally substituted with one or            more of: halo; —SCF₃; (C₁-C₆)alkyl, itself optionally            substituted with one or more halo; or (C₁-C₆)alkoxy, itself            optionally substituted with one or more halo;        -   —C(O)—(C₁-C₈)alkyl, wherein the alkyl is optionally            substituted with one or more halo;        -   —C(O)—(CH₂)_(n)—(C₃-C₁₀-cycloalkyl);        -   —C(O)—(CH₂)_(n)—NR^(k)R^(l), wherein R^(k) and R^(l) are            each independently:            -   hydrogen;            -   (C₁-C₆)alkyl, optionally substituted with one or more                halo;            -   (C₁-C₆)alkoxy, optionally substituted with one or more                halo; or            -   6 to 10 membered aryl, optionally substituted with one                or more of: halo; (C₁-C₆)alkyl, itself optionally                substituted with one or more halo; or (C₁-C₆)alkoxy,                itself optionally substituted with one or more halo;        -   —C(O)—(CH₂)_(n)—O—(C₁-C₆)alkyl; or        -   —C(O)—(CH₂)_(n)—O—(CH₂)_(n)-(6 to 10 membered aryl);-   R¹⁶ is: hydrogen; —(CH₂)_(n)OH; phenyl; —O—(C₁-C₆)alkyl; or    (C₁-C₆)alkyl, optionally substituted with one or more halo;-   R¹⁷ is: hydrogen; or (C₁-C₆)alkyl, optionally substituted with one    or ore halo; and-   n is 0, 1, or 2.

In one embodiment, R¹⁵ is hydrogen. In another embodiment. R¹⁵ is halo.In another embodiment. R¹⁵ is (C₁-C₆)alkyl, optionally substituted withone or more halo. In another embodiment, R¹⁵ is —(CH₂)_(n)OH orhydroxyl. In another embodiment. R¹⁵ is (C₁-C₆)alkoxy, optionallysubstituted with one or more halo.

In one embodiment, R¹⁵ is —(CH₂)_(n)NHR^(j). In one embodiment, whereinR¹⁵ is —(CH₂)_(n)NHR^(j), R^(j) is hydrogen. In another embodiment,R^(j) is (C₁-C₆)alkyl, optionally substituted with one or more halo. Inanother embodiment, R^(j) is —(CH₂)_(n)-(6 to 10 membered aryl). Inanother embodiment, R^(j) is —C(O)—(CH₂)_(n)-(6 to 10 membered aryl) or—C(O)—(CH₂)_(n)-(6 to 10 membered heteroaryl), wherein the aryl orheteroaryl is optionally substituted as described above. In anotherembodiment, R^(j) is —C(O)—(C₁-C₈)alkyl, wherein the alkyl is optionallysubstituted with one or more halo. In another embodiment. R^(j) is—C(O)—(CH₂)_(n)—(C₃-C₁₀-cycloalkyl). In another embodiment. R^(j) is—C(O)—(CH₂)_(n)—NR^(k)R^(l), wherein R^(k) and R^(l) are as describedabove. In another embodiment, R^(j) is —C(O)—(CH₂)_(n)—O—(C₁-C₆)alkyl.In another embodiment, R^(j) is —C(O)—(CH₂)_(n)—O—(CH₂)_(n)-(6 to 10membered aryl).

In one embodiment, R¹⁶ is hydrogen. In another embodiment, R¹⁶ is—(CH₂)_(n)OH or hydroxyl. In another embodiment, R¹⁶ is phenyl. Inanother embodiment, R¹⁶ is —O—(C₁-C₆)alkyl, optionally substituted withone or more halo. In another embodiment, R¹⁶ is (C₁-C₆)alkyl, optionallysubstituted with one or more halo.

In one embodiment. R¹⁷ is hydrogen. In another embodiment, R¹⁷ is(C₁-C₆)alkyl, optionally substituted with one or more halo.

In one embodiment, n is 0. In another embodiment, n is 1. In anotherembodiment, n is 2.

Compounds provided herein encompass any of the combinations of R¹⁵, R¹⁶,R¹⁷ and n described above.

In one specific embodiment, R¹⁵ is methyl. In another embodiment, R¹⁵ ishalo. In another embodiment, R¹⁵ is —CF₃. In another embodiment, R¹⁵ is—(CH₂)_(n)NHR^(j).

In one specific embodiment wherein R¹⁵ is —(CH₂)_(n)NHR^(j), R^(j) ishydrogen, and n is 0 or 1. In another embodiment wherein R¹⁵ is—(CH₂)_(n)NHR^(j), R^(j) is —C(O)—(O)—(C₁-C₆)alkyl.

In one specific embodiment, R¹⁶ is hydrogen. In another embodiment, R¹⁶is methyl. In another specific embodiment, R¹⁷ is hydrogen or methyl.

Specific compounds include, but are not limited to:

In another embodiment, provided herein are compounds of formula (VI):

and pharmaceutically acceptable salts, solvates, and stereoisomersthereof, wherein:

-   R¹⁸ is: hydrogen; halo; —(CH₂)_(n)OH; (C₁-C₆)alkyl, optionally    substituted with one or more halo; (C₁-C₆)alkoxy, optionally    substituted with one or more halo; or    -   —(CH₂)_(n)NHR^(m), wherein R^(m) is:        -   hydrogen;        -   (C₁-C₆)alkyl, optionally substituted with one or more halo;        -   —(CH₂)_(n)-(6 to 10 membered aryl);        -   —C(O)—(CH₂)_(n)-(6 to 10 membered aryl) or            —C(O)—(CH₂)_(n)-(6 to 10 membered heteroaryl), wherein the            aryl or heteroaryl is optionally substituted with one or            more of: halo; —SCF₃; (C₁-C₆)alkyl, itself optionally            substituted with one or more halo; or (C₁-C₆)alkoxy, itself            optionally substituted with one or more halo;        -   —C(O)—(C₁-C₈)alkyl, wherein the alkyl is optionally            substituted with one or more halo;        -   —C(O)—(CH₂)_(n)—(C₃-C₁₀-cycloalkyl);        -   —C(O)—(CH₂)—NR^(n)R^(o), wherein R^(n) and R^(o) are each            independently:            -   hydrogen;            -   (C₁-C₆)alkyl, optionally substituted with one or more                halo;            -   (C₁-C₆)alkoxy, optionally substituted with one or more                halo; or            -   6 to 10 membered aryl, optionally substituted with one                or more of: halo; (C₁-C₆)alkyl, itself optionally                substituted with one or more halo; or (C₁-C₆)alkoxy,                itself optionally substituted with one or more halo;        -   —C(O)—(CH₂)_(n)—O—(C₁-C₆)alkyl; or        -   —C(O)—(CH₂)_(n)—O—(CH₂)_(n)-(6 to 10 membered aryl);-   R¹⁹ is: hydrogen; —(CH₂)_(n)OH; phenyl; —O—(C₁-C₆)alkyl; or    (C₁-C₆)alkyl, optionally substituted with one or more halo:-   R²⁰ is: hydrogen; or (C₁-C₆)alkyl, optionally substituted with one    or more halo; and-   n is 0, 1, or 2.

In one embodiment. R¹⁸ is hydrogen. In another embodiment, R¹⁸ is halo.In another embodiment, R¹⁸ is (C₁-C₆)alkyl, optionally substituted withone or more halo. In another embodiment, R¹⁸ is —(CH₂)_(n)OH orhydroxyl. In another embodiment, R¹⁸ is (C₁-C₆)alkoxy, optionallysubstituted with one or more halo.

In one embodiment, R¹⁸ is —(CH₂)_(n)NHR^(m). In one embodiment, whereinR²⁸ is —(CH₂)_(n)NHR^(s), R^(s) is hydrogen. In another embodiment,R^(m) is (C₁-C₆)alkyl, optionally substituted with one or more halo. Inanother embodiment, R^(m) is —(CH₂)_(n)-(6 to 10 membered aryl). Inanother embodiment, R^(s) is —C(O)—(CH₂)_(n)-(6 to 10 membered aryl) or—C(O)—(CH₂)_(n)-(6 to 10 membered heteroaryl), wherein the aryl orheteroaryl is optionally substituted as described above. In anotherembodiment, R^(s) is —C(O)—(C₁-C₈)alkyl, wherein the alkyl is optionallysubstituted with one or more halo. In another embodiment, R^(m) is—C(O)—(CH₂)_(n)—(C₃-C₁₀-cycloalkyl). In another embodiment, R^(m) is—C(O)—(CH₂)_(n)—NR^(n)R^(o), wherein R^(n) and R^(o) are as describedabove. In another embodiment, R^(m) is —C(O)—(CH₂)_(n)—O—(C₁-C₆)alkyl.In another embodiment, R^(m) is —C(O)—(CH₂)_(n)—O—(CH₂)_(n)-(6 to 10membered aryl).

In one embodiment, R¹⁹ is hydrogen. In another embodiment, R¹⁹ is—(CH₂)_(n)OH or hydroxyl. In another embodiment, R¹⁹ is phenyl. Inanother embodiment, R¹ is —O—(C₁-C₆)alkyl, optionally substituted withone or more halo. In another embodiment, R¹⁹ is (C₁-C₆)alkyl, optionallysubstituted with one or more halo.

In one embodiment, R²⁰ is hydrogen. In another embodiment, R²⁰ is(C₁-C₆)alkyl, optionally substituted with one or more halo.

In one embodiment, n is 0. In another embodiment, n is 1. In anotherembodiment, n is 2.

Compounds provided herein encompass any of the combinations of R¹⁸, R¹⁹,R²⁰ and n described above.

In one specific embodiment, R¹⁸ is methyl. In another embodiment, R¹⁸ ishalo. In another embodiment, R¹⁸ is hydroxyl. In another embodiment, R¹⁸is —CF₃.

In one specific embodiment, R¹⁹ is hydrogen. In another embodiment, R¹⁹is methyl. In another specific embodiment, R²⁰ is hydrogen.

Specific compounds include, but are not limited to:

In another embodiment, provided herein are compounds of formula (VII):

and pharmaceutically acceptable salts, solvates, and stereoisomersthereof, wherein:

-   R²¹ is hydrogen;-   R²², R²³, and R²⁴ are each independently: halo; —(CH₂)_(n)OH;    (C₁-C₆)alkyl, optionally substituted with one or more halo;    (C₁-C₆)alkoxy, optionally substituted with one or more halo; or-   two of R²¹-R²⁴ together form a 5 to 6 membered ring, optionally    substituted with one or more of: halo; (C₁-C₆)alkyl, optionally    substituted with one or more halo; and (C₁-C₆)alkoxy, optionally    substituted with one or more halo;-   R²⁵ is: hydrogen; —(CH₂)_(n)OH; phenyl; —O—(C₁-C₆)alkyl; or    (C₁-C₆)alkyl, optionally substituted with one or more halo;-   R²⁶ is: hydrogen; or (C₁-C₆)alkyl, optionally substituted with one    or more halo; and-   n is 0, 1, or 2.

In one embodiment, two of R²²-R²⁴ are halo. In another embodiment, twoof R²²-R²⁴ are (C₁-C₆)alkyl, optionally substituted with one or morehalo. In another embodiment, two of R²²-R²⁴ are (C₁-C₆)alkoxy,optionally substituted with one or more halo.

In another embodiment, one of R²²-R²⁴ are is halo, and another one ofR²²-R²⁴ is (C₁-C₆)alkyl, optionally substituted with one or more halo.In another embodiment, one of R²²-R²⁴ is halo, and another one ofR²²-R²⁴ is (C₁-C₆)alkoxy, optionally substituted with one or more halo.

In another embodiment, one of R²²-R²⁴ is (C₁-C₆)alkoxy, optionallysubstituted with one or more halo, and another one of R²²-R²⁴ is(C₁-C₆)alkyl, optionally substituted with one or more halo.

In another embodiment, two of R²²-R²⁴ together form a 5 to 6 memberedring. In one specific embodiment, R²² and R²³ together form a 5 to 6membered ring. In one specific embodiment, R²² and R²³ together formphenyl ring. In another embodiment, the ring formed by R²² and R²³ isoptionally substituted with one or more of halo; (C₁-C₆)alkyl,optionally substituted with one or more halo; and (C₁-C₆)alkoxy,optionally substituted with one or more halo.

In one embodiment, R²⁵ is hydrogen. In another embodiment, R²⁵ is—(CH₂)_(n)OH or hydroxyl. In another embodiment, R²⁵ is phenyl. Inanother embodiment, R²⁵ is —O—(C₁-C₆)alkyl, optionally substituted withone or more halo. In another embodiment, R²⁵ is (C₁-C₆)alkyl, optionallysubstituted with one or more halo.

In one embodiment, R²⁶ is hydrogen. In another embodiment, R²⁶ is(C₁-C₆)alkyl, optionally substituted with one or more halo.

In one embodiment, n is 0. In another embodiment, n is 1. In anotherembodiment, n is 2.

Compounds provided herein encompass any of the combinations of R²¹, R²²,R²³, R²⁴, R²⁵, R²⁶, and n described above.

Specific compounds include, but are not limited to:

As used herein, and unless otherwise specified, the term“pharmaceutically acceptable salt” refers to salts prepared frompharmaceutically acceptable non-toxic acids, including inorganic acidsand organic acids. Suitable non-toxic acids include inorganic andorganic acids such as, but not limited to, acetic, alginic, anthranilic,benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic,formic, fumaric, furoic, gluconic, glutamic, glucorenic, galacturonic,glycidic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phenylacetic, propionic, phosphoric, salicylic, stearic, succinic,sulfanilic, sulfuric, tartaric acid, p-toluenesulfonic and the like. Inone embodiment, suitable are hydrochloric, hydrobromic, phosphoric, andsulfuric acids.

As used herein, and unless otherwise specified, the term “solvate” meansa compound that further includes a stoichiometric or non-stoichiometricamount of solvent bound by non-covalent inter molecular forces. Wherethe solvent is water, the solvate is a hydrate.

As used herein, and unless otherwise specified, the term “prodrug” meansa derivative of a compound that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide thecompound. Examples of prodrugs include, but are not limited to,compounds that comprise biohydrolyzable moieties such as biohydrolyzableamides, biohydrolyzable esters, biohydrolyzable carbamates,biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzablephosphate analogues. Other examples of prodrugs include compounds thatcomprise —NO, —NO, —ONO, or —ONO₂ moieties. Prodrugs can typically beprepared using well-known methods, such as those described in Burger'sMedicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E.Wolff ed., 5th ed. 1995), and Design of Prodrugs (H. Bundgaard ed.,Elselvier, New York 1985).

As used herein, and unless otherwise specified, the terms“biohydrolyzable carbamate,” “biohydrolyzable carbonate,”“biohydrolyzable ureide” and “biohydrolyzable phosphate” mean acarbamate, carbonate, ureide and phosphate, respectively, of a compoundthat either: 1) does not interfere with the biological activity of thecompound but can confer upon that compound advantageous properties invivo, such as uptake, duration of action, or onset of action; or 2) isbiologically inactive but is converted in vivo to the biologicallyactive compound. Examples of biohydrolyzable carbamates include, but arenot limited to, carbamates that include lower alkylamine, substitutedethylenediamine, aminoacid, hydroxyalkylamine, heterocyclic andheteroaromatic amine, and polyether amine moieties.

As used herein, and unless otherwise specified, the term “stereoisomer”encompasses all enantiomerically/stereomerically pure andenantiomerically/stereomerically enriched compounds provided herein.

As used herein and unless otherwise indicated, the term “stereomericallypure” means a composition that comprises one stereoisomer of a compoundand is substantially free of other stereoisomers of that compound. Forexample, a stereomerically pure composition of a compound having onechiral center will be substantially free of the opposite enantiomer ofthe compound. A stereomerically pure composition of a compound havingtwo chiral centers will be substantially free of other diastereomers ofthe compound. A typical stereomerically pure compound comprises greaterthan about 80% by weight of one stereoisomer of the compound and lessthan about 20% by weight of other stereoisomers of the compound, greaterthan about 90% by weight of one stereoisomer of the compound and lessthan about 10% by weight of the other stereoisomers of the compound,greater than about 95% by weight of one stereoisomer of the compound andless than about 5% by weight of the other stereoisomers of the compound,or greater than about 97% by weight of one stereoisomer of the compoundand less than about 3% by weight of the other stereoisomers of thecompound.

As used herein and unless otherwise indicated, the term “stereomericallyenriched” means a composition that comprises greater than about 55% byweight of one stereoisomer of a compound, greater than about 60% byweight of one stereoisomer of a compound, greater than about 70% byweight, or greater than about 80% by weight of one stereoisomer of acompound.

As used herein, and unless otherwise indicated, the term“enantiomerically pure” means a stereomerically pure composition of acompound having one chiral center. Similarly, the term “enantiomericallyenriched” means a stereomerically enriched composition of a compoundhaving one chiral center.

As used herein, and unless otherwise indicated, the term “alkyl” refersto a saturated straight chain or branched hydrocarbon having a number ofcarbon atoms as specified herein. Representative saturated straightchain alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl,and -n-hexyl; while saturated branched alkyls include -isopropyl,-sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl,3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,2,3-dimethylbutyl, and the like. The term “alkyl” also encompassescycloalkyl.

As used herein, and unless otherwise specified, the term “cycloalkyl”means a specie of alkyl containing from 3 to 15 carbon atoms, withoutalternating or resonating double bonds between carbon atoms. It maycontain from 1 to 4 rings. Examples of unsubstituted cycloalkylsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and adamantyl. A cycloalkyl may be substituted with one ormore of the substituents.

As used herein, the term “aryl” means a carbocyclic aromatic ringcontaining from 5 to 14 ring atoms. The ring atoms of a carbocyclic arylgroup are all carbon atoms. Aryl ring structures include compoundshaving one or more ring structures such as mono-, bi-, or tricycliccompounds as well as benzo-fused carbocyclic moieties such as5,6,7,8-tetrahydronaphthyl and the like. Specifically, the aryl group isa monocyclic ring or bicyclic ring. Representative aryl groups includephenyl, anthracenyl, fluorenyl, indenyl, azulenyl, phenanthrenyl andnaphthyl.

It should be noted that if there is a discrepancy between a depictedstructure and a name given that structure, the depicted structure is tobe accorded more weight. In addition, if the stereochemistry of astructure or a portion of a structure is not indicated with, forexample, bold or dashed lines, the structure or portion of the structureis to be interpreted as encompassing all stereoisomers of it.

4.2 METHODS OF TREATMENT, PREVENTION AND MANAGEMENT

Provided herein are methods of treating, preventing, and/or managingvarious diseases or disorders using a compound provided herein, or apharmaceutically acceptable salt, solvate (e.g., hydrate), prodrug,clathrate, or stereoisomer thereof. Without being limited by aparticular theory, compounds provided herein can control angiogenesis orinhibit the production of certain cytokines including, but not limitedto, TNF-α, IL-1β, IL-12, IL-18, GM-CSF, and/or IL-6. Without beinglimited by a particular theory, compounds provided herein can stimulatethe production of cetain other cytokines including IL-10, and also actas a costimulatory signal for T cell activation, resulting in increasedproduction of cytokines such as, but not limited to, IL-12 and/or IFN-γ.In addition, compounds provided herein can enhance the effects of NKcells and antibody-mediated cellular cytotoxicity (ADCC). Further,compounds provided herein may be immunomodulatory and/or cytotoxic, andthus, may be useful as chemotherapeutic agents. Consequently, withoutbeing limited by a particular theory, some or all of suchcharacteristics possessed by the compounds provided herein may renderthem useful in treating, managing, and/or preventing various diseases ordisorders.

Examples of diseases or disorders include, but are not limited to,cancer, disorders associated with angiogenesis, pain including, but notlimited to, Complex Regional Pain Syndrome (“CRPS”), MacularDegeneration (“MD”) and related syndromes, skin diseases, pulmonarydisorders, asbestos-related disorders, parasitic diseases,immunodeficiency disorders. CNS disorders, CNS injury, atherosclerosisand related disorders, dysfunctional sleep and related disorders,hemoglobinopathy and related disorders (e.g., anemia), TNFα relateddisorders, and other various diseases and disorders.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” refer to the eradication or amelioration of adisease or disorder, or of one or more symptoms associated with thedisease or disorder. In certain embodiments, the terms refer tominimizing the spread or worsening of the disease or disorder resultingfrom the administration of one or more prophylactic or therapeuticagents to a subject with such a disease or disorder. In someembodiments, the terms refer to the administration of a compoundprovided herein, with or without other additional active agent, afterthe onset of symptoms of the particular disease.

As used herein, and unless otherwise specified, the terms “prevent,”“preventing” and “prevention” refer to the prevention of the onset,recurrence or spread of a disease or disorder, or of one or moresymptoms thereof. In certain embodiments, the terms refer to thetreatment with or administration of a compound provided herein, with orwithout other additional active compound, prior to the onset ofsymptoms, particularly to patients at risk of disease or disordersprovided herein. The terms encompass the inhibition or reduction of asymptom of the particular disease. Patients with familial history of adisease in particular are candidates for preventive regimens in certainembodiments. In addition, patients who have a history of reccurringsymptoms are also potential candidates for the prevention. In thisregard, the term “prevention” may be interchangeably used with the term“prophylactic treatment.”

As used herein, and unless otherwise specified, the terms “manage,”“managing” and “management” refer to preventing or slowing theprogression, spread or worsening of a disease or disorder, or of one ormore symptoms thereof. Often, the beneficial effects that a subjectderives from a prophylactic and/or therapeutic agent do not result in acure of the disease or disorder. In this regard, the term “managing”encompasses treating a patient who had suffered from the particulardisease in an attempt to prevent or minimize the recurrence of thedisease.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment or management of a disease ordisorder, or to delay or minimize one or more symptoms associated withthe disease or disorder. A therapeutically effective amount of acompound means an amount of therapeutic agent, alone or in combinationwith other therapies, which provides a therapeutic benefit in thetreatment or management of the disease or disorder. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease ordisorder, or enhances the therapeutic efficacy of another therapeuticagent.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease or disorder, or prevent its recurrence. A prophylacticallyeffective amount of a compound means an amount of therapeutic agent,alone or in combination with other agents, which provides a prophylacticbenefit in the prevention of the disease. The term “prophylacticallyeffective amount” can encompass an amount that improves overallprophylaxis or enhances the prophylactic efficacy of anotherprophylactic agent.

Examples of cancer and precancerous conditions include, but are notlimited to, those described in U.S. Pat. Nos. 6,281,230 and 5,635,517 toMuller et al., in various U.S. patent publications to Zeldis, includingpublication nos. 2004/0220144A1, published Nov. 4, 2004 (Treatment ofMyelodysplastic Syndrome); 2004/0029832A1, published Feb. 12, 2004(Treatment of Various Types of Cancer); and 2004/0087546, published May6, 2004 (Treatment of Myeloproliferative Diseases). Examples alsoinclude those described in WO 2004/103274, published Dec. 2, 2004. Allof these references are incorporated herein in their entireties byreference.

Specific examples of cancer include, but are not limited to, cancers ofthe skin, such as melanoma; lymph node; breast; cervix; uterus;gastrointestinal tract; lung; ovary; prostate; colon; rectum; mouth;brain; head and neck; throat; testes; kidney; pancreas; bone; spleen;liver; bladder; larynx; nasal passages; and AIDS-related cancers. Thecompounds are also useful for treating cancers of the blood and bonemarrow, such as multiple myeloma and acute and chronic leukemias, forexample, lymphoblastic, myelogenous, lymphocytic, and myelocyticleukemias. The compounds provided herein can be used for treating,preventing or managing either primary or metastatic tumors.

Other specific cancers include, but are not limited to, advancedmalignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma,multiple brain metastase, glioblastoma multiforms, glioblastoma, brainstem glioma, poor prognosis malignant brain tumor, malignant glioma,recurrent malignant glioma, anaplastic astrocytoma, anaplasticoligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C& D colorectal cancer, unresectable colorectal carcinoma, metastatichepatocellular carcinoma, Kaposi's sarcoma, karotype acute myeloblasticleukemia, chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma,non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Celllymphoma, diffuse large B-Cell lymphoma, low grade follicular lymphoma,metastatic melanoma (localized melanoma, including, but not limited to,ocular melanoma), malignant mesothelioma, malignant pleural effusionmesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma,gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneousvasculitis, Langerhans cell histiocytosis, leiomyosarcoma,fibrodysplasia ossificans progressive, hormone refractory prostatecancer, resected high-risk soft tissue sarcoma, unrescectablehepatocellular carcinoma, Waldenstrom's macroglobulinemia, smolderingmyeloma, indolent myeloma, fallopian tube cancer, androgen independentprostate cancer, androgen dependent stage IV non-metastatic prostatecancer, hormone-insensitive prostate cancer, chemotherapy-insensitiveprostate cancer, papillary thyroid carcinoma, follicular thyroidcarcinoma, medullary thyroid carcinoma, and leiomyoma. In a specificembodiment, the cancer is metastatic. In another embodiment, the canceris refractory or resistance to chemotherapy or radiation.

In one embodiment, provided herein are methods of treating, preventingor managing various forms of leukemias such as chronic lymphocyticleukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia,acute myelogenous leukemia and acute myeloblastic leukemia, includingleukemias that are relapsed, refractory or resistant, as disclosed inU.S. publication no. 2006/0030594, published Feb. 9, 2006, which isincorporated in its entirety by reference.

The term “leukemia” refers malignant neoplasms of the blood-formingtissues. The leukemia includes, but is not limited to, chroniclymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblasticleukemia, acute myelogenous leukemia and acute myeloblastic leukemia.The leukemia can be relapsed, refractory or resistant to conventionaltherapy. The term “relapsed” refers to a situation where patients whohave had a remission of leukemia after therapy have a return of leukemiacells in the marrow and a decrease in normal blood cells. The term“refractory or resistant” refers to a circumstance where patients, evenafter intensive treatment, have residual leukemia cells in their marrow.

In another embodiment, provided herein are methods of treating,preventing or managing various types of lymphomas, includingNon-Hodgkin's lymphoma (NHL). The term “lymphoma” refers a heterogenousgroup of neoplasms arising in the reticuloendothelial and lymphaticsystems. “NHL” refers to malignant monoclonal proliferation of lymphoidcells in sites of the immune system, including lymph nodes, bone marrow,spleen, liver and gastrointestinal tract. Examples of NHL include, butare not limited to, mantle cell lymphoma (MCL), lymphocytic lymphoma ofintermediate differentiation, intermediate lymphocytic lymphoma (ILL),diffuse poorly differentiated lymphocytic lymphoma (PDL), centrocyticlymphoma, diffuse small-cleaved cell lymphoma (DSCCL), follicularlymphoma, and any type of the mantle cell lymphomas that can be seenunder the microscope (nodular, diffuse, blastic and mentle zonelymphoma).

Examples of diseases and disorders associated with, or characterized by,undesired angiogenesis include, but are not limited to, inflammatorydiseases, autoimmune diseases, viral diseases, genetic diseases,allergic diseases, bacterial diseases, ocular neovascular diseases,choroidal neovascular diseases, retina neovascular diseases, andrubeosis (neovascularization of the angle). Specific examples of thediseases and disorders associated with, or characterized by, undesiredangiogenesis include, but are not limited to, arthritis, endometriosis,Crohn's disease, heart failure, advanced heart failure, renalimpairment, endotoxemia, toxic shock syndrome, osteoarthritis,retrovirus replication, wasting, meningitis, silica-induced fibrosis,asbestos-induced fibrosis, veterinary disorder, malignancy-associatedhypercalcemia, stroke, circulatory shock, periodontitis, gingivitis,macrocytic anemia, refractory anemia, and 5q-deletion syndrome.

Examples of pain include, but are not limited to those described in U.S.patent publication no. 2005/0203142, published Sep. 15, 2005, which isincorporated herein by reference. Specific types of pain include, butare not limited to, nociceptive pain, neuropathic pain, mixed pain ofnociceptive and neuropathic pain, visceral pain, migraine, headache andpost-operative pain.

Examples of nociceptive pain include, but are not limited to, painassociated with chemical or thermal burns, cuts of the skin, contusionsof the skin, osteoarthritis, rheumatoid arthritis, tendonitis, andmyofascial pain.

Examples of neuropathic pain include, but are not limited to, CRPS typeI, CRPS type II, reflex sympathetic dystrophy (RSD), reflexneurovascular dystrophy, reflex dystrophy, sympathetically maintainedpain syndrome, causalgia, Sudeck atrophy of bone, algoneurodystrophy,shoulder hand syndrome, post-traumatic dystrophy, trigeminal neuralgia,post herpetic neuralgia, cancer related pain, phantom limb pain,fibromyalgia, chronic fatigue syndrome, spinal cord injury pain, centralpost-stroke pain, radiculopathy, diabetic neuropathy, post-stroke pain,luetic neuropathy, and other painful neuropathic conditions such asthose induced by drugs such as vincristine and velcade.

As used herein, the terms “complex regional pain syndrome,” “CRPS” and“CRPS and related syndromes” mean a chronic pain disorder characterizedby one or more of the following: pain, whether spontaneous or evoked,including allodynia (painful response to a stimulus that is not usuallypainful) and hyperalgesia (exaggerated response to a stimulus that isusually only mildly painful); pain that is disproportionate to theinciting event (e.g., years of severe pain after an ankle sprain);regional pain that is not limited to a single peripheral nervedistribution; and autonomic dysregulation (e.g., edema, alteration inblood flow and hyperhidrosis) associated with trophic skin changes (hairand nail growth abnormalities and cutaneous ulceration).

Examples of MD and related syndromes include, but are not limited to,those described in U.S. patent publication no. 2004/0091455, publishedMay 13, 2004″ which is incorporated herein by reference. Specificexamples include, but are not limited to, atrophic (dry) MD, exudative(wet) MD, age-related maculopathy (ARM), choroidal neovascularisation(CNVM), retinal pigment epithelium detachment (PED), and atrophy ofretinal pigment epithelium (RPE).

Examples of skin diseases include, but are not limited to, thosedescribed in U.S. publication no. 2005/0214328A1, published Sep. 29,2005, which is incorporated herein by reference. Specific examplesinclude, but are not limited to, keratoses and related symptoms, skindiseases or disorders characterized with overgrowths of the epidermis,acne, and wrinkles.

As used herein, the term “keratosis” refers to any lesion on theepidermis marked by the presence of circumscribed overgrowths of thehorny layer, including but not limited to actinic keratosis, seborrheickeratosis, keratoacanthoma, keratosis follicularis (Darier disease),inverted follicular keratosis, palmoplantar keratoderma (PPK, keratosispalmaris et plantaris), keratosis pilaris, and stucco keratosis. Theterm “actinic keratosis” also refers to senile keratosis, keratosissenilis, verruca senilis, plana senilis, solar keratosis, keratoderma orkeratoma. The term “seborrheic keratosis” also refers to seborrheicwart, senile wart, or basal cell papilloma. Keratosis is characterizedby one or more of the following symptoms: rough appearing, scaly,erythematous papules, plaques, spicules or nodules on exposed surfaces(e.g., face, hands, ears, neck, legs and thorax), excrescences ofkeratin referred to as cutaneous horns, hyperkeratosis, telangiectasias,elastosis, pigmented lentigines, acanthosis, parakeratosis,dyskeratoses, papillomatosis, hyperpigmentation of the basal cells,cellular atypia, mitotic figures, abnormal cell-cell adhesion, denseinflammatory infiltrates and small prevalence of squamous cellcarcinomas.

Examples of skin diseases or disorders characterized with overgrowths ofthe epidermis include, but are not limited to, any conditions, diseasesor disorders marked by the presence of overgrowths of the epidermis,including but not limited to, infections associated with papillomavirus, arsenical keratoses, sign of Leser-Trélat, warty dyskeratoma(WD), trichostasis spinulosa (TS), erythrokeratodermia variabilis (EKV),ichthyosis fetalis (harlequin ichthyosis), knuckle pads, cutaneousmelanoacanthoma, porokeratosis, psoriasis, squamous cell carcinoma,confluent and reticulated papillomatosis (CRP), acrochordons, cutaneoushorn, cowden disease (multiple hamartoma syndrome), dermatosis papulosanigra (DPN), epidermal nevus syndrome (ENS), ichthyosis vulgaris,molluscum contagiosum, prurigo nodularis, and acanthosis nigricans (AN).

Examples of pulmonary disorders include, but are not limited to, thosedescribed in U.S. publication no. 2005/0239842A 1, published Oct. 27,2005, which is incorporated herein by reference. Specific examplesinclude pulmonary hypertension and related disorders. Examples ofpulmonary hypertension and related disorders include, but are notlimited to: primary pulmonary hypertension (PPH); secondary pulmonaryhypertension (SPH); familial PPH; sporadic PPH; precapillary pulmonaryhypertension; pulmonary arterial hypertension (PAH); pulmonary arteryhypertension; idiopathic pulmonary hypertension; thrombotic pulmonaryarteriopathy (TPA); plexogenic pulmonary arteriopathy; functionalclasses I to IV pulmonary hypertension; and pulmonary hypertensionassociated with, related to, or secondary to, left ventriculardysfunction, mitral valvular disease, constrictive pericarditis, aorticstenosis, cardiomyopathy, mediastinal fibrosis, anomalous pulmonaryvenous drainage, pulmonary venoocclusive disease, collagen vasulardisease, congenital heart disease, HIV virus infection, drugs and toxinssuch as fenfluramines, congenital heart disease, pulmonary venoushypertension, chronic obstructive pulmonary disease, interstitial lungdisease, sleep-disordered breathing, alveolar hypoventilation disorder,chronic exposure to high altitude, neonatal lung disease,alveolar-capillary dysplasia, sickle cell disease, other coagulationdisorder, chronic thromboemboli, connective tissue disease, lupusincluding systemic and cutaneous lupus, schistosomiasis, sarcoidosis orpulmonary capillary hemangiomatosis.

Examples of asbestos-related disorders include, but not limited to,those described in U.S. publication no. 2005/0100529, published May 12,2005, which is incorporated herein by reference. Specific examplesinclude, but are not limited to, mesothelioma, asbestosis, malignantpleural effusion, benign exudative effusion, pleural plaques, pleuralcalcification, diffuse pleural thickening, rounded atelectasis, fibroticmasses, and lung cancer.

Examples of parasitic diseases include, but are not limited to, thosedescribed in U.S. publication no. 2006/0154880, published Jul. 13, 2006,which is incorporated herein by reference. Parasitic diseases includediseases and disorders caused by human intracellular parasites such as,but not limited to, P. falcifarium, P. ovale, P. vivax, P. malariae, L.donovari, L. infantum, L. aethiopica, L. major, L. tropica, L. mexicana,L. braziliensis, T. Gondii, B. microti, B. divergens, B. coli, C.parvum, C. cayetanensis, E. histolytica, I. belli, S. mansonii, S.haematobium, Trvpanosoma ssp., Toxoplasma ssp., and O. volvulus. Otherdiseases and disorders caused by non-human intracellular parasites suchas, but not limited to, Babesia bovis, Babesia canis, Babesia Gibsoni,Besnoitia darlingi, Cytauxzoon felis, Eimeria ssp., Hammondia ssp., andTheileria ssp., are also encompassed. Specific examples include, but arenot limited to, malaria, babesiosis, trypanosomiasis, leishmaniasis,toxoplasmosis, meningoencephalitis, keratitis, amebiasis, giardiasis,cryptosporidiosis, isosporiasis, cyclosporiasis, microsporidiosis,ascariasis, trichuriasis, ancylostomiasis, strongyloidiasis,toxocariasis, trichinosis, lymphatic filariasis, onchocerciasis,filariasis, schistosomiasis, and dermatitis caused by animalschistosomes.

Examples of immunodeficiency disorders include, but are not limited to,those described in U.S. publication no. 2006/0188475, published Aug. 24,2006. Specific examples include, but not limited to, adenosine deaminasedeficiency, antibody deficiency with normal or elevated Igs,ataxia-tenlangiectasia, bare lymphocyte syndrome, common variableimmunodeficiency, Ig deficiency with hyper-IgM, Ig heavy chaindeletions. IgA deficiency, immunodeficiency with thymoma, reticulardysgenesis, Nezelof syndrome, selective IgG subclass deficiency,transient hypogammaglobulinemia of infancy. Wistcott-Aldrich syndrome,X-linked agammaglobulinemia, X-linked severe combined immunodeficiency.

Examples of CNS disorders include, but are not limited to, thosedescribed in U.S. publication no. 2005/0143344, published Jun. 30, 2005,which is incorporated herein by reference. Specific examples include,but are not limited to, include, but are not limited to, AmyotrophicLateral Sclerosis, Alzheimer Disease, Parkinson Disease, Huntington'sDisease, Multiple Sclerosis other neuroimmunological disorders such asTourette Syndrome, delerium, or disturbances in consciousness that occurover a short period of time, and amnestic disorder, or discreet memoryimpairments that occur in the absence of other central nervous systemimpairments.

Examples of CNS injuries and related syndromes include, but are notlimited to, those described in U.S. publication no. 2006/0122228,published Jun. 8, 2006, which is incorporated herein by reference.Specific examples include, but are not limited to, CNS injury/damage andrelated syndromes, include, but are not limited to, primary braininjury, secondary brain injury, traumatic brain injury, focal braininjury, diffuse axonal injury, head injury, concussion, post-concussionsyndrome, cerebral contusion and laceration, subdural hematoma,epidermal hematoma, post-traumatic epilepsy, chronic vegetative state,complete SCI, incomplete SCI, acute SCI, subacute SCI, chronic SCI,central cord syndrome, Brown-Sequard syndrome, anterior cord syndrome,conus medullaris syndrome, cauda equina syndrome, neurogenic shock,spinal shock, altered level of consciousness, headache, nausea, emesis,memory loss, dizziness, diplopia, blurred vision, emotional lability,sleep disturbances, irritability, inability to concentrate, nervousness,behavioral impairment, cognitive deficit, and seizure.

Other disease or disorders include, but not limited to, viral, genetic,allergic, and autoimmune diseases. Specific examples include, but notlimited to, HIV, hepatitis, adult respiratory distress syndrome, boneresorption diseases, chronic pulmonary inflammatory diseases,dermatitis, cystic fibrosis, septic shock, sepsis, endotoxic shock,hemodynamic shock, sepsis syndrome, post ischemic reperfusion injury,meningitis, psoriasis, fibrotic disease, cachexia, graft versus hostdisease, graft rejection, auto-immune disease, rheumatoid spondylitis,Crohn's disease, ulcerative colitis, inflammatory-bowel disease,multiple sclerosis, systemic lupus erythrematosus, ENL in leprosy,radiation damage, cancer, asthma, or hyperoxic alveolar injury.

Examples of atherosclerosis and related conditions include, but are notlimited to, those disclosed in U.S. publication no. 2002/0054899,published May 9, 2002, which is incorporated herein by reference.Specific examples include, but are not limited to, all forms ofconditions involving atherosclerosis, including restenosis aftervascular intervention such as angioplasty, stenting, atherectomy andgrafting. All fowls of vascular intervention are contemplated herein,including diseases of the cardiovascular and renal system, such as, butnot limited to, renal angioplasty, percutaneous coronary intervention(PCI), percutaneous transluminal coronary angioplasty (PTCA), carotidpercutaneous transluminal angioplasty (PTA), coronary by-pass grafting,angioplasty with stent implantation, peripheral percutaneoustransluminal intervention of the iliac, femoral or popliteal arteries,and surgical intervention using impregnated artificial grafts. Thefollowing chart provides a listing of the major systemic arteries thatmay be in need of treatment, all of which are contemplated herein:

Artery Body Areas Supplied Axillary Shoulder and axilla Brachial Upperarm Brachiocephalic Head, neck, and arm Celiac Divides into leftgastric, splenic, and hepatic arteries Common carotid Neck Common iliacDivides into external and internal iliac arteries Coronary Heart Deepfemoral Thigh Digital Fingers Dorsalis pedis Foot External carotid Neckand external head regions External iliac Femoral artery Femoral ThighGastric Stomach Hepatic Liver, gallbladder, pancreas, and duodenumInferior mesenteric Descending colon, rectum, and pelvic wall Internalcarotid Neck and internal head regions Internal iliac Rectum, urinarybladder, external genitalia, buttocks muscles, uterus and vagina Leftgastric Esophagus and stomach Middle sacral Sacrum Ovarian OvariesPalmar arch Hand Peroneal Calf Popliteal Knee Posterior tibial CalfPulmonary Lungs Radial Forearm Renal Kidney Splenic Stomach, pancreas,and spleen Subclavian Shoulder Superior Pancreas, small intestine,ascending and transverse mesenteric colon Testicular Testes UlnarForearm

Examples of dysfunctional sleep and related syndromes include, but arenot limited to, those disclosed in U.S. publication no. 2005/0222209A1,published Oct. 6, 2005, which is incorporated herein by reference.Specific examples include, but are not limited to, snoring, sleep apnea,insomnia, narcolepsy, restless leg syndrome, sleep terrors, sleepwalking sleep eating, and dysfunctional sleep associated with chronicneurological or inflammatory conditions. Chronic neurological orinflammatory conditions, include, but are not limited to, ComplexRegional Pain Syndrome, chronic low back pain, musculoskeletal pain,arthritis, radiculopathy, pain associated with cancer, fibromyalgia,chronic fatigue syndrome, visceral pain, bladder pain, chronicpancreatitis, neuropathies (diabetic, post-herpetic, traumatic orinflammatory), and neurodegenerative disorders such as Parkinson'sDisease, Alzheimer's Disease, amyotrophic lateral sclerosis, multiplesclerosis, Huntington's Disease, bradykinesia; muscle rigidity;parkinsonian tremor; parkinsonian gait; motion freezing; depression;defective long-term memory, Rubinstein-Taybi syndrome (RTS); dementia;postural instability; hypokinetic disorders; synuclein disorders;multiple system atrophies; striatonigral degeneration;olivopontocerebellar atrophy; Shy-Drager syndrome; motor neuron diseasewith parkinsonian features; Lewy body dementia; Tau pathology disorders;progressive supranuclear palsy; corticobasal degeneration;frontotemporal dementia; amyloid pathology disorders; mild cognitiveimpairment; Alzheimer disease with parkinsonism; Wilson disease;Hallervorden-Spatz disease; Chediak-Hagashi disease; SCA-3spinocerebellar ataxia; X-linked dystonia parkinsonism; prion disease;hyperkinetic disorders; chorea; ballismus; dystonia tremors; AmyotrophicLateral Sclerosis (ALS); CNS trauma and myoclonus.

Examples of hemoglobinopathy and related disorders include, but are notlimited to, those described in U.S. publication no. 2005/0143420A1,published Jun. 30, 2005, which is incorporated herein by reference.Specific examples include, but are not limited to, hemoglobinopathy,sickle cell anemia, and any other disorders related to thedifferentiation of CD34+ cells.

Examples of TNFα related disorders include, but are not limited to,those described in WO 98/03502 and WO 98/54170, both of which areincorporated herein in their entireties by reference. Specific examplesinclude, but are not limited to: endotoxemia or toxic shock syndrome;cachexia; adult respiratory distress syndrome; bone resorption diseasessuch as arthritis; hypercalcemia; Graft versus Host Reaction; cerebralmalaria; inflammation; tumor growth; chronic pulmonary inflammatorydiseases; reperfusion injury; myocardial infarction; stroke; circulatoryshock; rheumatoid arthritis; Crohn's disease; HIV infection and AIDS;other disorders such as rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, psoriatic arthritis and other arthritic conditions,septic shock, septis, endotoxic shock, graft versus host disease,wasting, Crohn's disease, ulcerative colitis, multiple sclerosis,systemic lupus erythromatosis, ENL in leprosy, HIV, AIDS, andopportunistic infections in AIDS; disorders such as septic shock,sepsis, endotoxic shock, hemodynamic shock and sepsis syndrome, postischemic reperfusion injury, malaria, mycobacterial infection,meningitis, psoriasis, congestive heart failure, fibrotic disease,cachexia, graft rejection, oncogenic or cancerous conditions, asthma,autoimmune disease, radiation damages, and hyperoxic alveolar injury;viral infections, such as those caused by the herpes viruses; viralconjunctivitis; or atopic dermatitis.

In other embodiments, the use of compounds provided herein in variousimmunological applications, in particular, as vaccine adjuvants,particularly anticancer vaccine adjuvants, as disclosed in U.S.Publication No. 2007/0048327, published Mar. 1, 2007, which isincorporated herein in its entirety by reference, is also encompassed.These embodiments also relate to the uses of compounds provided hereinin combination with vaccines to treat or prevent cancer or infectiousdiseases, and other various uses of immunomodulatory compounds such asreduction or desensitization of allergic reactions.

Doses of a compound provided herein, or a pharmaceutically acceptablesalt, solvate, clathrate, stereoisomer or prodrug thereof, varydepending on factors such as: specific indication to be treated,prevented, or managed; age and condition of a patient; and amount ofsecond active agent used, if any. Generally, a compound provided herein,or a pharmaceutically acceptable salt, solvate, clathrate, stereoisomeror prodrug thereof, may be used in an amount of from about 0.1 mg toabout 500 mg per day, and can be adjusted in a conventional fashion(e.g., the same amount administered each day of the treatment,prevention or management period), in cycles (e.g., one week on, one weekoff), or in an amount that increases or decreases over the course oftreatment, prevention, or management. In other embodiments, the dose canbe from about 1 mg to about 300 mg, from about 0.1 mg to about 150 mg,from about 1 mg to about 200 mg, from about 10 mg to about 100 mg, fromabout 0.1 mg to about 50 mg, from about 1 mg to about 50 mg, from about10 mg to about 50 mg, from about 20 mg to about 30 mg, or from about 1mg to about 20 mg.

4.3 SECOND ACTIVE AGENTS

A compound provided herein, or a pharmaceutically acceptable salt,solvate, prodrug, clathrate, or stereoisomer thereof, can be combinedwith other pharmacologically active compounds (“second active agents”)in methods and compositions provided herein. Certain combinations maywork synergistically in the treatment of particular types diseases ordisorders, and conditions and symptoms associated with such diseases ordisorders. A compound provided herein, or a pharmaceutically acceptablesalt, solvate, clathrate, stereoisomer or prodrug thereof, can also workto alleviate adverse effects associated with certain second activeagents, and vice versa.

One or more second active ingredients or agents can be used in themethods and compositions provided herein. Second active agents can belarge molecules (e.g., proteins) or small molecules (e.g., syntheticinorganic, organometallic, or organic molecules).

Examples of large molecule active agents include, but are not limitedto, hematopoietic growth factors, cytokines, and monoclonal andpolyclonal antibodies. Specific examples of the active agents areanti-CD40 monoclonal antibodies (such as, for example, SGN-40); histonedeacetylyase inhibitors (such as, for example, SAHA and LAQ 824);heat-shock protein-90 inhibitors (such as, for example, 17-AAG);insulin-like growth factor-1 receptor kinase inhibitors; vascularendothelial growth factor receptor kinase inhibitors (such as, forexample, PTK787); insulin growth factor receptor inhibitors;lysophosphatidic acid acyltransrerase inhibitors; IkB kinase inhibitors;p38MAPK inhibitors; EGFR inhibitors (such as, for example, gefitinib anderlotinib HCL); HER-2 antibodies (such as, for example, trastuzumab(Herceptin) and pertuzumab (Omnitarg™)); VEGFR antibodies (such as, forexample, bevacizumab (Avastin™)); VEGFR inhibitors (such as, forexample, flk-1 specific kinase inhibitors, SU5416 and ptk787/zk222584);P13K inhibitors (such as, for example, wortmannin); C-Met inhibitors(such as, for example, PHA-665752); monoclonal antibodies (such as, forexample, rituximab (Rituxan®), tositumomab (Bexxar®), edrecolomab(Panorex®) and G250); and anti-TNF-α antibodies. Examples of smallmolecule active agents include, but are not limited to, anticanceragents and antibiotics (e.g., clarithromycin).

Specific second active compounds that can be combined with compoundsprovided herein vary depending on the specific indication to be treated,prevented or managed.

For instance, for the treatment, prevention or management of cancer,second active agents include, but are not limited to: semaxanib;cyclosporin; etanercept; doxycycline; bortezomib; acivicin; aclarubicin;acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine;ambomycin; ametantrone acetate; amsacrine; anastrozole; anthramycin;asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat;benzodepa; bicalutamide; bisantrene hydrochloride; bisnatide dimesylate;bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol; celecoxib;chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicinhydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguaninemesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin;edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin;enpromate; epipropidine; epirubicin hydrochloride; erbulozole;esorubicin hydrochloride; estramustine; estramustine phosphate sodium;etanidazole; etoposide; etoposide phosphate; etoprine; fadrozolehydrochloride; fazarabine; fenretinide; floxuridine; fludarabinephosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium;gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicinhydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan;irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolideacetate; liarozole hydrochloride; lometrexol sodium; lomustine;losoxantrone hydrochloride; masoprocol; maytansine; mechlorethaminehydrochloride; megestrol acetate; melengestrol acetate; melphalan;menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolicacid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel;pegaspargase; peliomycin; pentamustine; peplomycin sulfate;perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride;pyrazofurin; riboprine; safingol; safingol hydrochloride; semustine;simtrazene; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; taxotere; tegafur;teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicinhydrochloride.

Other second agents include, but are not limited to: 20-epi-1,25dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists;altretamine; ambamustine; amidox; amifostine; aminolevulinic acid;amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;angiogenesis inhibitors; antagonist D; antagonist G; antarelix;anti-dorsalizing morphogenetic protein-1; antiandrogen, prostaticcarcinoma; antiestrogen; antineoplaston; antisense oligonucleotides;aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators;apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3;azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol;batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine;beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid;bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;bisnafide; bistratene A; bizelesin; bretlate; bropirimine; budotitane;buthionine sulfoximine; calcipotriol; calphostin C; camptothecinderivatives; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel;docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene;dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine;edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride;estramustine analogue; estrogen agonists; estrogen antagonists;etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine;fenretinide; filgrastim; finasteride; flavopiridol; flezelastine;fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex;formestane; fostriecin; fotemustine; gadolinium texaphyrin; galliumnitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine;glutathione inhibitors; hepsulfam; heregulin; hexamethylenebisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene;idramantone; ilmofosine; ilomastat; imatinib (Gleevec®), imiquimod;immunostimulant peptides; insulin-like growth factor-1 receptorinhibitor; interferon agonists; interferons; interleukins; iobenguane;iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole;isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F;lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinansulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocytealpha interferon; leuprolide+estrogen+progesterone; leuprorelin;levamisole; liarozole; linear polyamine analogue; lipophilicdisaccharide peptide; lipophilic platinum compounds; lissoclinamide 7;lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lyticpeptides; maitansine; mannostatin A; marimastat; masoprocol; maspin;matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril;merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor;mifepristone; miltefosine; mirimostim; mitoguazone; mitolactol;mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; Erbitux, humanchorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wallsk; mopidamol; mustard anticancer agent; mycaperoxide B; mycobacterialcell wall extract; myriaporone; N-acetyldinaline; N-substitutedbenzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin;naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid;nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant;nitrullyn; oblimersen (Genasense®); O6-benzylguanine; octreotide;okicenone; oligonucleotides; onapristone; ondansetron; ondansetron;oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin;oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives;palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene;parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfatesodium; pentostatin; pentrozole; perflubron; perfosfamide; perillylalcohol; phenazinomycin; phenylacetate; phosphatase inhibitors;picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetinA; placetin B; plasminogen activator inhibitor; platinum complex;platinum compounds; platinum-triamine complex; porfimer sodium;porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;proteasome inhibitors; protein A-based immune modulator; protein kinaseC inhibitor; protein kinase C inhibitors, microalgal; protein tyrosinephosphatase inhibitors; purine nucleoside phosphorylase inhibitors;purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethyleneconjugate; raf antagonists; raltitrexed; ramosetron; ras farnesylprotein transferase inhibitors; ras inhibitors; ras-GAP inhibitor;retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;ribozymes; RII retinamide; rohitukine; romurtide; roquinimex; rubiginoneB1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim;Sdi 1 mimetics; semustine; senescence derived inhibitor 1; senseoligonucleotides; signal transduction inhibitors; sizofiran; sobuzoxane;sodium borocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stipiamide; stromelysininhibitors; sulfinosine; superactive vasoactive intestinal peptideantagonist; suradista; suramin; swainsonine; tallimustine; tamoxifenmethiodide; tauromustine; tazarotene; tecogalan sodium; tegafur;tellurapyrylium; telomerase inhibitors; temoporfin; teniposide;tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline;thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietinreceptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyletiopurpurin; tirapazamine; titanocene bichloride; topsentin;toremifene; translation inhibitors; tretinoin; triacetyluridine;triciribine; trimetrexate; triptorelin; tropisetron; turosteride;tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;urogenital sinus-derived growth inhibitory factor; urokinase receptorantagonists; vapreotide; variolin B; velaresol; veramine; verdins;verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone;zeniplatin; zilascorb; and zinostatin stimalamer.

Specific second active agents include, but are not limited to,2-methoxyestradiol, telomestatin, inducers of apoptosis in mutiplemyeloma cells (such as, for example, TRAIL), statins, semaxanib,cyclosporin, etanercept, doxycycline, bortezomib, oblimersen(Genasense®), remicade, docetaxel, celecoxib, melphalan, dexamethasone(Decadron'), steroids, gemcitabine, cisplatinum, temozolomide,etoposide, cyclophosphamide, temodar, carboplatin, procarbazine,gliadel, tamoxifen, topotecan, methotrexate, Arise, taxol, taxotere,fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alpha,pegylated interferon alpha (e.g., PEG INTRON-A), capecitabine,cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin,cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2. GM-CSF,dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin,busulphan, prednisone, bisphosphonate, arsenic trioxide, vincristine,doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, estramustinesodium phosphate (Emcyt®), sulindac, and etoposide.

In another embodiment, examples of specific second agents according tothe indications to be treated, prevented, or managed can be found in thefollowing references, all of which are incorporated herein in theirentireties: U.S. Pat. Nos. 6,281,230 and 5,635,517; and U.S. publicationnos. 2004/0220144, 2004/0190609, 2004/0087546, 2005/0203142,2004/0091455, 2005/0100529, 2005/0214328, 2005/0239842, 2006/0154880,2006/0188475, 2006/0122228, and 2005/0143344.

Examples of second active agents that may be used for the treatment,prevention and/or management of pain include, but are not limited to,conventional therapeutics used to treat or prevent pain such asantidepressants, anticonvulsants, antihypertensives, anxiolytics,calcium channel blockers, muscle relaxants, non-narcotic analgesics,opioid analgesics, anti-inflammatories, cox-2 inhibitors,immunomodulatory agents, alpha-adrenergic receptor agonists orantagonists, immunosuppressive agents, corticosteroids, hyperbaricoxygen, ketamine, other anesthetic agents, NMDA antagonists, and othertherapeutics found, for example, in the Physician's Desk Reference 2003.Specific examples include, but are not limited to, salicylic acidacetate (Aspirin®), celecoxib (Celebrex®), Enbrel®, ketamine, gabapentin(Neurontin®), phenyloin (Dilantin®), carbamazepine (Tegretol®),oxcarbazepine (Trileptal®), valproic acid (Depakene®), morphine sulfate,hydromorphone, prednisone, griseofulvin, penthonium, alendronate,dyphenhydramide, guanethidine, ketorolac (Acular®), thyrocalcitonin,dimethylsulfoxide (DMSO), clonidine (Catapress®), bretylium, ketanserin,reserpine, droperidol, atropine, phentolamine, bupivacaine, lidocaine,acetaminophen, nortriptyline (Pamelor®), amitriptyline (Elavil®),imipramine (Tofranil®), doxepin (Sinequan®), clomipramine (Anafranil®),fluoxetine (Prozac®), sertraline (Zoloft®), naproxen, nefazodone(Serzone®), venlafaxine (Effexor®), trazodone (Desyrel®), bupropion(Wellbutrin®), mexiletine, nifedipine, propranolol, tramadol,lamotrigine, vioxx, ziconotide, ketamine, dextromethorphan,benzodiazepines, baclofen, tizanidine and phenoxybenzamine.

Examples of second active agents that may be used for the treatment,prevention and/or management of macular degeneration and relatedsyndromes include, but are not limited to, a steroid, a lightsensitizer, an integrin, an antioxidant, an interferon, a xanthinederivative, a growth hormone, a neutrotrophic factor, a regulator ofneovascularization, an anti-VEGF antibody, a prostaglandin, anantibiotic, a phytoestrogen, an anti-inflammatory compound or anantiangiogenesis compound, or a combination thereof. Specific examplesinclude, but are not limited to, verteporfin, purlytin, an angiostaticsteroid, rhuFab, interferon-2α, pentoxifylline, tin etiopurpurin,motexafin, lucentis, lutetium, 9-fluoro-11,21-dihydroxy-16,17-1-methylethylidinebis(oxy)pregna-1,4-diene-3,20-dione, latanoprost(see U.S. Pat. No. 6,225,348), tetracycline and its derivatives,rifamycin and its derivatives, macrolides, metronidazole (U.S. Pat. Nos.6,218,369 and 6,015,803), genistein, genistin, 6′-O-Mal genistin,6′-O-Ac genistin, daidzein, daidzin, 6′-O-Mal daidzin, 6′-O-Ac daidzin,glycitein, glycitin, 6′-O-Mal glycitin, biochanin A, formononetin (U.S.Pat. No. 6,001,368), triamcinolone acetonide, dexamethasone (U.S. Pat.No. 5,770,589), thalidomide, glutathione (U.S. Pat. No. 5,632,984),basic fibroblast growth factor (bFGF), transforming growth factor b(TGF-b), brain-derived neurotrophic factor (BDNF), plasminogen activatorfactor type 2 (PAI-2), EYE 101 (Eyetech Pharmaceuticals). LY333531 (EliLilly), Miravant, and RETISERT implant (Bausch & Lomb). All of thereferences cited herein are incorporated in their entireties byreference.

Examples of second active agents that may be used for the treatment,prevention and/or management of skin diseases include, but are notlimited to, keratolytics, retinoids, α-hydroxy acids, antibiotics,collagen, botulinum toxin, interferon, steroids, and immunomodulatoryagents. Specific examples include, but are not limited to,5-fluorouracil, masoprocol, trichloroacetic acid, salicylic acid, lacticacid, ammonium lactate, urea, tretinoin, isotretinoin, antibiotics,collagen, botulinum toxin, interferon, corticosteroid, transretinoicacid and collagens such as human placental collagen, animal placentalcollagen, Dermalogen, AlloDerm, Fascia, Cymetra, Autologen, Zyderm,Zyplast, Resoplast, and Isolagen.

Examples of second active agents that may be used for the treatment,prevention and/or management of pulmonary hepertension and relateddisorders include, but are not limited to, anticoagulants, diuretics,cardiac glycosides, calcium channel blockers, vasodilators, prostacyclinanalogues, endothelin antagonists, phosphodiesterase inhibitors (e.g.,PDE V inhibitors), endopeptidase inhibitors, lipid lowering agents,thromboxane inhibitors, and other therapeutics known to reduce pulmonaryartery pressure. Specific examples include, but are not limited to,warfarin (Coumadin®), a diuretic, a cardiac glycoside, digoxin-oxygen,diltiazem, nifedipine, a vasodilator such as prostacyclin (e.g.,prostaglandin 12 (PG12), epoprostenol (EPO, Floran®), treprostinil(Remodulin®), nitric oxide (NO), bosentan (Tracleer®), amlodipine,epoprostenol (Floran®), treprostinil (Remodulin®), prostacyclin,tadalafil simvastatin (Zocor®), omapatrilat (Vanlev®), irbesartan(Avapro®), pravastatin (Pravachol®), digoxin, L-arginine, iloprost,betaprost, and sildenafil (Viagra®).

Examples of second active agents that may be used for the treatment,prevention and/or management of asbestos-related disorders include, butare not limited to, anthracycline, platinum, alkylating agent,oblimersen (Genasense®), cisplatinum, cyclophosphamide, temodar,carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate,taxotere, irinotecan, capecitabine, cisplatin, thiotepa, fludarabine,carboplatin, liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel,vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid,palmitronate, biaxin, busulphan, prednisone, bisphosphonate, arsenictrioxide, vincristine, doxorubicin (Doxil®), paclitaxel, ganciclovir,adriamycin, bleomycin, hyaluronidase, mitomycin C, mepacrine, thiotepa,tetracycline and gemcitabine.

Examples of second active agents that may be used for the treatment,prevention and/or management of parasitic diseases include, but are notlimited to, chloroquine, quinine, quinidine, pyrimethamine,sulfadiazine, doxycycline, clindamycin, mefloquine, halofantrine,primaquine, hydroxychloroquine, proguanil, atovaquone, azithromycin,suramin, pentamidine, melarsoprol, nifurtimox, benznidazole,amphotericin B, pentavalent antimony compounds (e.g., sodiumstiboglucuronate), interfereon gamma, itraconazole, a combination ofdead promastigotes and BCG, leucovorin, corticosteroids, sulfonamide,spiramycin, IgG (serology), trimethoprim, and sulfamethoxazole.

Examples of second active agents that may be used for the treatment,prevention and/or management of immunodeficiency disorders include, butare not limited to: antibiotics (therapeutic or prophylactic) such as,but not limited to, ampicillin, tetracycline, penicillin,cephalosporins, streptomycin, kanamycin, and erythromycin; antiviralssuch as, but not limited to, amantadine, rimantadine, acyclovir, andribavirin; immunoglobulin; plasma; immunologic enhancing drugs such as,but not limited to, levami sole and isoprinosine; biologics such as, butnot limited to, gammaglobulin, transfer factor, interleukins, andinterferons; hormones such as, but not limited to, thymic; and otherimmunologic agents such as, but not limited to, B cell stimulators(e.g., BAFF/BlyS), cytokines (e.g., IL-2, IL-4, and IL-5), growthfactors (e.g., TGF-α), antibodies (e.g., anti-CD40 and IgM),oligonucleotides containing unmethylated CpG motifs, and vaccines (e.g.,viral and tumor peptide vaccines).

Examples of second active agents that may be used for the treatment,prevention and/or management of CNS disorders include, but are notlimited to: opioids; a dopamine agonist or antagonist, such as, but notlimited to, Levodopa, L-DOPA, cocaine, α-methyl-tyrosine, reserpine,tetrabenazine, benzotropine, pargyline, fenodolpam mesylate,cabergoline, pramipexole dihydrochloride, ropinorole, amantadinehydrochloride, selegiline hydrochloride, carbidopa, pergolide mesylate,Sinemet CR, and Symmetrel; a MAO inhibitor, such as, but not limited to,iproniazid, clorgyline, phenelzine and isocarboxazid; a COMT inhibitor,such as, but not limited to, tolcapone and entacapone; a cholinesteraseinhibitor, such as, but not limited to, physostigmine saliclate,physostigmine sulfate, physostigmine bromide, meostigmine bromide,neostigmine methylsulfate, ambenonim chloride, edrophonium chloride,tacrine, pralidoxime chloride, obidoxime chloride, trimedoxime bromide,diacetyl monoxim, endrophonium, pyridostigmine, and demecarium; ananti-inflammatory agent, such as, but not limited to, naproxen sodium,diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin,diflunisal, etodolac, meloxicam, ibuprofen, ketoprofen, nabumetone,refecoxib, methotrexate, leflunomide, sulfasalazine, gold salts, Rho-DImmune Globulin, mycophenylate mofetil, cyclosporine, azathioprine,tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylicacid, methyl salicylate, diflunisal, salsalate, olsalazine,sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic acid,meclofenamate sodium, tolmetin, ketorolac, dichlofenac, flurbinprofen,oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam,tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine,apazone, zileuton, aurothioglucose, gold sodium thiomalate, auranofin,methotrexate, colchicine, allopurinol, probenecid, sulfinpyrazone andbenzbromarone or betamethasone and other glucocorticoids; and anantiemetic agent, such as, but not limited to, metoclopromide,domperidone, prochlorperazine, promethazine, chlorpromazine,trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucinemonoethanolamine, alizapride, azasetron, benzquinamide, bietanautine,bromopride, buclizine, clebopride, cyclizine, dimenhydrinate,diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone,oxyperndyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol,thiethylperazine, thioproperazine, tropisetron, and a mixture thereof.

Examples of second active agents that may be used for the treatment,prevention and/or management of CNS injuries and related syndromesinclude, but are not limited to, immunomodulatory agents,immunosuppressive agents, antihypertensives, anticonvulsants,fibrinolytic agents, antiplatelet agents, antipsychotics,antidepressants, benzodiazepines, buspirone, amantadine, and other knownor conventional agents used in patients with CNS injury/damage andrelated syndromes. Specific examples include, but are not limited to:steroids (e.g., glucocorticoids, such as, but not limited to,methylprednisolone, dexamethasone and betamethasone); ananti-inflammatory agent, including, but not limited to, naproxen sodium,diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin,diflunisal, etodolac, meloxicam, ibuprofen, ketoprofen, nabumetone,refecoxib, methotrexate, leflunomide, sulfasalazine, gold salts, RHo-DImmune Globulin, mycophenylate mofetil, cyclosporine, azathioprine,tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylicacid, methyl salicylate, diflunisal, salsalate, olsalazine,sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic acid,meclofenamate sodium, tolmetin, ketorolac, dichlofenac, flurbinprofen,oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam,tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine,apazone, zileuton, aurothioglucose, gold sodium thiomalate, auranofin,methotrexate, colchicine, allopurinol, probenecid, sulfinpyrazone andbenzbromarone; a cAMP analog including, but not limited to, db-cAMP; anagent comprising a methylphenidate drug, which comprises1-threo-methylphenidate, d-threo-methylphenidate,dl-threo-methylphenidate, 1-erythro-methylphenidate,d-erythro-methylphenidate, dl-erythro-methylphenidate, and a mixturethereof; and a diuretic agent such as, but not limited to, mannitol,furosemide, glycerol, and urea.

Examples of second active agent that may be used for the treatment,prevention and/or management of dysfunctional sleep and relatedsyndromes include, but are not limited to, a tricyclic antidepressantagent, a selective serotonin reuptake inhibitor, an antiepileptic agent(gabapentin, pregabalin, carbamazepine, oxcarbazepine, levitiracetam,topiramate), an antiaryhthmic agent, a sodium channel blocking agent, aselective inflammatory mediator inhibitor, an opioid agent, a secondimmunomodulatory compound, a combination agent, and other known orconventional agents used in sleep therapy. Specific examples include,but are not limited to, Neurontin, oxycontin, morphine, topiramate,amitryptiline, nortryptiline, carbamazepine, Levodopa, L-DOPA, cocaine,α-methyl-tyrosine, reserpine, tetrabenazine, benzotropine, pargyline,fenodolpam mesylate, cabergoline, pramipexole dihydrochloride,ropinorole, amantadine hydrochloride, selegiline hydrochloride,carbidopa, pergolide mesylate, Sinemet CR, Symmetrel, iproniazid,clorgyline, phenelzine, isocarboxazid, tolcapone, entacapone,physostigmine saliclate, physostigmine sulfate, physostigmine bromide,meostigmine bromide, neostigmine methylsulfate, ambenonim chloride,edrophonium chloride, tacrine, pralidoxime chloride, obidoxime chloride,trimedoxime bromide, diacetyl monoxim, endrophonium, pyridostigmine,demecarium, naproxen sodium, diclofenac sodium, diclofenac potassium,celecoxib, sulindac, oxaprozin, diflunisal, etodolac, meloxicam,ibuprofen, ketoprofen, nabumetone, refecoxib, methotrexate, leflunomide,sulfasalazine, gold salts, RHo-D Immune Globulin, mycophenylate mofetil,cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab,salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal,salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin,sulindac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac,dichlofenac, flurbinprofen, oxaprozin, piroxicam, meloxicam,ampiroxicam, droxicam, pivoxicam, tenoxicam, phenylbutazone,oxyphenbutazone, antipyrine, aminopyrine, apazone, zileuton,aurothioglucose, gold sodium thiomalate, auranofin, methotrexate,colchicine, allopurinol, probenecid, sulfinpyrazone, benzbromarone,betamethasone and other glucocorticoids, metoclopromide, domperidone,prochlorperazine, promethazine, chlorpromazine, trimethobenzamide,ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine,alizapride, azasetron, benzquinamide, bietanautine, bromopride,buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol,dolasetron, meclizine, methallatal, metopimazine, nabilone, oxypemdyl,pipamazine, scopolamine, sulpiride, tetrahydrocannabinol,thiethylperazine, thioproperazine, tropisetron, and a mixture thereof.

Examples of second active agents that may be used for the treatment,prevention and/or management of hemoglobinopathy and related disordersinclude, but are not limited to: interleukins, such as IL-2 (includingrecombinant IL-II (“rIL2”) and canarypox IL-2), IL-10, IL-12, and IL-18;interferons, such as interferon alfa-2a, interferon alfa-2b, interferonalfa-n1, interferon alfa-n3, interferon beta-I a, and interferon gamma-Ib; and G-CSF; hydroxyurea; butyrates or butyrate derivatives; nitrousoxide; hydroxy urea; HEMOXIN™ (NIPRISAN™; see U.S. Pat. No. 5,800,819);Gardos channel antagonists such as clotrimazole and triaryl methanederivatives; Deferoxamine; protein C; and transfusions of blood, or of ablood substitute such as Hemospan™ or Hemospan™ PS (Sangart).

Administration of a compound provided herein, or a pharmaceuticallyacceptable salt, solvate, clathrate, stereoisomer or prodrug thereof,and the second active agents to a patient can occur simultaneously orsequentially by the same or different routes of administration. Thesuitability of a particular route of administration employed for aparticular active agent will depend on the active agent itself (e.g.,whether it can be administered orally without decomposing prior toentering the blood stream) and the disease being treated. One ofadministration for compounds provided herein is oral. Routes ofadministration for the second active agents or ingredients are known tothose of ordinary skill in the art. See, e.g., Physicians' DeskReference (60^(th) ed., 2006).

In one embodiment, the second active agent is administered intravenouslyor subcutaneously and once or twice daily in an amount of from about 1to about 1000 mg, from about 5 to about 500 mg, from about 10 to about350 mg, or from about 50 to about 200 mg. The specific amount of thesecond active agent will depend on the specific agent used, the type ofdisease being treated or managed, the severity and stage of disease, andthe amount(s) of compounds provided herein and any optional additionalactive agents concurrently administered to the patient.

As discussed elsewhere herein, also encompassed is a method of reducing,treating and/or preventing adverse or undesired effects associated withconventional therapy including, but not limited to, surgery,chemotherapy, radiation therapy, hormonal therapy, biological therapyand immunotherapy. Compounds provided herein and other activeingredients can be administered to a patient prior to, during, or afterthe occurrence of the adverse effect associated with conventionaltherapy.

4.4 CYCLING THERAPY

In certain embodiments, the prophylactic or therapeutic agents providedherein are cyclically administered to a patient. Cycling therapyinvolves the administration of an active agent for a period of time,followed by a rest (i.e., discontinuation of the administration) for aperiod of time, and repeating this sequential administration. Cyclingtherapy can reduce the development of resistance to one or more of thetherapies, avoid or reduce the side effects of one of the therapies,and/or improve the efficacy of the treatment.

Consequently, in one embodiment, a compound provided herein isadministered daily in a single or divided doses in a four to six weekcycle with a rest period of about a week or two weeks. Cycling therapyfurther allows the frequency, number, and length of dosing cycles to beincreased. Thus, another embodiment encompasses the administration of acompound provided herein for more cycles than are typical when it isadministered alone. In yet another embodiment, a compound providedherein is administered for a greater number of cycles than wouldtypically cause dose-limiting toxicity in a patient to whom a secondactive ingredient is not also being administered.

In one embodiment, a compound provided herein is administered daily andcontinuously for three or four weeks at a dose of from about 0.1 mg toabout 500 mg per day, followed by a rest of one or two weeks. In otherembodiments, the dose can be from about 1 mg to about 300 mg, from about0.1 mg to about 150 mg, from about 1 mg to about 200 mg, from about 10mg to about 100 mg, from about 0.1 mg to about 50 mg, from about 1 mg toabout 50 mg, from about 10 mg to about 50 mg, from about 20 mg to about30 mg, or from about 1 mg to about 20 mg, followed by a rest.

In one embodiment, a compound provided herein and a second activeingredient are administered orally, with administration of the compoundprovided herein occurring 30 to 60 minutes prior to the second activeingredient, during a cycle of four to six weeks. In another embodiment,the combination of a compound provided herein and a second activeingredient is administered by intravenous infusion over about 90 minutesevery cycle.

Typically, the number of cycles during which the combination treatmentis administered to a patient will be from about one to about 24 cycles,from about two to about 16 cycles, or from about four to about threecycles.

4.5 PHARMACEUTICAL COMPOSITIONS AND DOSAGE FORMS

Pharmaceutical compositions can be used in the preparation ofindividual, single unit dosage forms. Pharmaceutical compositions anddosage forms provided herein comprise a compound provided herein, or apharmaceutically acceptable salt, solvate, stereoisomer, clathrate, orprodrug thereof. Pharmaceutical compositions and dosage forms canfurther comprise one or more excipients.

Pharmaceutical compositions and dosage forms provided herein can alsocomprise one or more additional active ingredients. Examples of optionalsecond, or additional, active ingredients are disclosed in Section 4.3,above.

Single unit dosage forms provided herein are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), topical (e.g., eye drops or other ophthalmicpreparations), transdermal or transcutaneous administration to apatient. Examples of dosage forms include, but are not limited to:tablets; caplets; capsules, such as soft elastic gelatin capsules;cachets; troches; lozenges; dispersions; suppositories; powders;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; eye drops or other ophthalmic preparations suitable fortopical administration; and sterile solids (e.g., crystalline oramorphous solids) that can be reconstituted to provide liquid dosageforms suitable for parenteral administration to a patient.

The composition, shape, and type of dosage forms will typically varydepending on their use. For example, a dosage form used in the acutetreatment of a disease may contain larger amounts of one or more of theactive ingredients it comprises than a dosage form used in the chronictreatment of the same disease. Similarly, a parenteral dosage form maycontain smaller amounts of one or more of the active ingredients itcomprises than an oral dosage form used to treat the same disease. Theseand other ways in which specific dosage forms are used will vary fromone another will be readily apparent to those skilled in the art. See,e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing,Easton Pa. (1990).

In one embodiment, pharmaceutical compositions and dosage forms compriseone or more excipients. Suitable excipients are well known to thoseskilled in the art of pharmacy, and non-limiting examples of suitableexcipients are provided herein. Whether a particular excipient issuitable for incorporation into a pharmaceutical composition or dosageform depends on a variety of factors well known in the art including,but not limited to, the way in which the dosage form will beadministered to a patient. For example, oral dosage forms such astablets may contain excipients not suited for use in parenteral dosageforms. The suitability of a particular excipient may also depend on thespecific active ingredients in the dosage form. For example, thedecomposition of some active ingredients may be accelerated by someexcipients such as lactose, or when exposed to water. Active ingredientsthat comprise primary or secondary amines are particularly susceptibleto such accelerated decomposition. Consequently, provided arepharmaceutical compositions and dosage forms that contain little, ifany, lactose other mono- or di-saccharides. As used herein, the term“lactose-free” means that the amount of lactose present, if any, isinsufficient to substantially increase the degradation rate of an activeingredient.

Lactose-free compositions can comprise excipients that are well known inthe art and are listed, for example, in the U.S. Pharmacopeia (USP)25-NF20 (2002). In general, lactose-free compositions comprise activeingredients, a binder/filler, and a lubricant in pharmaceuticallycompatible and pharmaceutically acceptable amounts. In one embodiment,lactose-free dosage forms comprise active ingredients, microcrystallinecellulose, pre-gelatinized starch, and magnesium stearate.

Also provided are anhydrous pharmaceutical compositions and dosage formscomprising active ingredients, since water can facilitate thedegradation of some compounds. For example, the addition of water (e.g.,5%) is widely accepted in the pharmaceutical arts as a means ofsimulating long-term storage in order to determine characteristics suchas shelf-life or the stability of formulations over time. See, e.g.,Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed.,Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect, water and heataccelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms can be preparedusing anhydrous or low moisture containing ingredients and low moistureor low humidity conditions. Pharmaceutical compositions and dosage formsthat comprise lactose and at least one active ingredient that comprisesa primary or secondary amine are preferably anhydrous if substantialcontact with moisture and/or humidity during manufacturing, packaging,and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are, in one embodiment, packaged using materials known toprevent exposure to water such that they can be included in suitableformulary kits. Examples of suitable packaging include, but are notlimited to, hermetically sealed foils, plastics, unit dose containers(e.g., vials), blister packs, and strip packs.

Also provided are pharmaceutical compositions and dosage forms thatcomprise one or more compounds that reduce the rate by which an activeingredient will decompose. Such compounds, which are referred to hereinas “stabilizers,” include, but are not limited to, antioxidants such asascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the amounts and specific typesof active ingredients in a dosage form may differ depending on factorssuch as, but not limited to, the route by which it is to be administeredto patients. In one embodiment, dosage forms comprise a compoundprovided herein in an amount of from about 0.10 to about 500 mg. Inother embodiments, dosage forms comprise a compound provided herein inan amount of about 0.1, 1, 2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50,100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.

In other embodiments, dosage forms comprise the second active ingredientin an amount of 1 to about 1000 mg, from about 5 to about 500 mg, fromabout 10 to about 350 mg, or from about 50 to about 200 mg. Of course,the specific amount of the second active agent will depend on thespecific agent used, the diseases or disorders being treated or managed,and the amount(s) of a compound provided herein, and any optionaladditional active agents concurrently administered to the patient.

4.5.1 Oral Dosage Forms

Pharmaceutical compositions that are suitable for oral administrationcan be provided as discrete dosage forms, such as, but not limited to,tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g.,flavored syrups). Such dosage forms contain predetermined amounts ofactive ingredients, and may be prepared by methods of pharmacy wellknown to those skilled in the art. See generally, Remington'sPharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).

Oral dosage forms provided herein are prepared by combining the activeingredients in an intimate admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. For example, excipients suitablefor use in oral liquid or aerosol dosage forms include, but are notlimited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

In one embodiment, oral dosage forms are tablets or capsules, in whichcase solid excipients are employed. In another embodiment, tablets canbe coated by standard aqueous or nonaqueous techniques. Such dosageforms can be prepared by any of the methods of pharmacy. In general,pharmaceutical compositions and dosage forms are prepared by uniformlyand intimately admixing the active ingredients with liquid carriers,finely divided solid carriers, or both, and then shaping the productinto the desired presentation if necessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms providedherein include, but are not limited to, binders, fillers, disintegrants,and lubricants. Binders suitable for use in pharmaceutical compositionsand dosage forms include, but are not limited to, corn starch, potatostarch, or other starches, gelatin, natural and synthetic gums such asacacia, sodium alginate, alginic acid, other alginates, powderedtragacanth, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethyl cellulose calcium, sodiumcarboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose,pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos.2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Anspecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103™ and Starch 1500LM.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms provided herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions is, in oneembodiment, present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form. Disintegrants may be used inthe compositions to provide tablets that disintegrate when exposed to anaqueous environment. Tablets that contain too much disintegrant maydisintegrate in storage, while those that contain too little may notdisintegrate at a desired rate or under the desired conditions. Thus, asufficient amount of disintegrant that is neither too much nor toolittle to detrimentally alter the release of the active ingredients maybe used to form solid oral dosage forms. The amount of disintegrant usedvaries based upon the type of formulation, and is readily discernible tothose of ordinary skill in the art. In one embodiment, pharmaceuticalcompositions comprise from about 0.5 to about 15 weight percent ofdisintegrant, or from about 1 to about 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, agar-agar, alginic acid, calciumcarbonate, microcrystalline cellulose, croscarmellose sodium,crospovidone, polacrilin potassium, sodium starch glycolate, potato ortapioca starch, other starches, pre-gelatinized starch, other starches,clays, other algins, other celluloses, gums, and mixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, calcium stearate, magnesiumstearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol,polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate,talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zincstearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.Additional lubricants include, for example, a syloid silica gel(AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, Md.), acoagulated aerosol of synthetic silica (marketed by Degussa Co. ofPlano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants may be used in an amount of less than about 1 weight percentof the pharmaceutical compositions or dosage forms into which they areincorporated.

In one embodiment, a solid oral dosage form comprises a compoundprovided herein, anhydrous lactose, microcrystalline cellulose,polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, andgelatin.

4.5.2 Controlled Release Dosage Forms

Active ingredients provided herein can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active agents provided herein. In one embodiment, provided aresingle unit dosage forms suitable for oral administration such as, butnot limited to, tablets, capsules, gelcaps, and caplets that are adaptedfor controlled-release.

In one embodiment, controlled-release pharmaceutical products improvedrug therapy over that achieved by their non-controlled counterparts. Inanother embodiment, the use of a controlled-release preparation inmedical treatment is characterized by a minimum of drug substance beingemployed to cure or control the condition in a minimum amount of time.Advantages of controlled-release formulations include extended activityof the drug, reduced dosage frequency, and increased patient compliance.In addition, controlled-release formulations can be used to affect thetime of onset of action or other characteristics, such as blood levelsof the drug, and can thus affect the occurrence of side (e.g., adverse)effects.

In another embodiment, the controlled-release formulations are designedto initially release an amount of drug (active ingredient) that promptlyproduces the desired therapeutic or prophylactic effect, and graduallyand continually release of other amounts of drug to maintain this levelof therapeutic or prophylactic effect over an extended period of time.In one embodiment, in order to maintain a constant level of drug in thebody, the drug can be released from the dosage form at a rate that willreplace the amount of drug being metabolized and excreted from the body.Controlled-release of an active ingredient can be stimulated by variousconditions including, but not limited to, pH, temperature, enzymes,water, or other physiological conditions or compounds.

4.5.3 Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. In someembodiments, administration of a parenteral dosage form bypassespatients' natural defenses against contaminants, and thus, in theseembodiments, parenteral dosage forms are sterile or capable of beingsterilized prior to administration to a patient. Examples of parenteraldosage forms include, but are not limited to, solutions ready forinjection, dry products ready to be dissolved or suspended in apharmaceutically acceptable vehicle for injection, suspensions ready forinjection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage formsare well known to those skilled in the art. Examples include, but arenot limited to: Water for Injection USP; aqueous vehicles such as, butnot limited to, Sodium Chloride Injection, Ringer's Injection, DextroseInjection, Dextrose and Sodium Chloride Injection, and Lactated Ringer'sInjection; water-miscible vehicles such as, but not limited to, ethylalcohol, polyethylene glycol, and polypropylene glycol; and non-aqueousvehicles such as, but not limited to, corn oil, cottonseed oil, peanutoil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms. For example, cyclodextrin and its derivativescan be used to increase the solubility of a compound provided herein.See, e.g., U.S. Pat. No. 5,134,127, which is incorporated herein byreference.

4.5.4 Topical and Mucosal Dosage Forms

Topical and mucosal dosage forms provided herein include, but are notlimited to, sprays, aerosols, solutions, emulsions, suspensions, eyedrops or other ophthalmic preparations, or other forms known to one ofskill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16thand 18th eds., Mack Publishing, Easton Pa. (1980 & 1990); andIntroduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger,Philadelphia (1985). Dosage forms suitable for treating mucosal tissueswithin the oral cavity can be formulated as mouthwashes or as oral gels.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide topical and mucosal dosage forms encompassedherein are well known to those skilled in the pharmaceutical arts, anddepend on the particular tissue to which a given pharmaceuticalcomposition or dosage form will be applied. In one embodiment,excipients include, but are not limited to, water, acetone, ethanol,ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate,isopropyl palmitate, mineral oil, and mixtures thereof to formsolutions, emulsions or gels, which are non-toxic and pharmaceuticallyacceptable. Moisturizers or humectants can also be added topharmaceutical compositions and dosage forms. Examples of additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa.(1980 & 1990).

The pH of a pharmaceutical composition or dosage form may also beadjusted to improve delivery of one or more active ingredients. Also,the polarity of a solvent carrier, its ionic strength, or tonicity canbe adjusted to improve delivery. Compounds such as stearates can also beadded to pharmaceutical compositions or dosage forms to alter thehydrophilicity or lipophilicity of one or more active ingredients so asto improve delivery. In other embodiments, stearates can serve as alipid vehicle for the formulation, as an emulsifying agent orsurfactant, or as a delivery-enhancing or penetration-enhancing agent.In other embodiments, salts, solvates, prodrugs, clathrates, orstereoisomers of the active ingredients can be used to further adjustthe properties of the resulting composition.

4.6 KITS

In one embodiment, active ingredients provided herein are notadministered to a patient at the same time or by the same route ofadministration. In another embodiment, provided are kits which cansimplify the administration of appropriate amounts of activeingredients.

In one embodiment, a kit comprises a dosage form of a compound providedherein. Kits can further comprise additional active ingredients such asoblimersen (Genasense®), melphalan, G-CSF, GM-CSF, EPO, topotecan,dacarbazine, irinotecan, taxotere, IFN, COX-2 inhibitor, pentoxifylline,ciprotloxacin, dexamethasone, IL2, IL8, IL18. Ara-C, vinorelbine,isotretinoin, 13 cis-retinoic acid, or a pharmacologically active mutantor derivative thereof, or a combination thereof. Examples of theadditional active ingredients include, but are not limited to, thosedisclosed herein (see, e.g., section 4.3).

In other embodiments, kits can further comprise devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, drip bags, patches, and inhalers.

Kits can further comprise cells or blood for transplantation as well aspharmaceutically acceptable vehicles that can be used to administer oneor more active ingredients. For example, if an active ingredient isprovided in a solid form that must be reconstituted for parenteraladministration, the kit can comprise a sealed container of a suitablevehicle in which the active ingredient can be dissolved to form aparticulate-free sterile solution that is suitable for parenteraladministration. Examples of pharmaceutically acceptable vehiclesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

5. EXAMPLES

Certain embodiments of the invention are illustrated by the followingnon-limiting examples.

5.1 3-(2,6-DIMETHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

To a stirred mixture of 2-amino-5-methylbenzoic acid (4.8 g, 32 mmol)and imidazole (2.6 g, 38 mmol) in acetonitrile (100 mL), was addedacetyl chloride (2.7 mL, 38 mmol) at room temperature. The mixture wasstirred at room temperature overnight. To the mixture, was added3-amino-piperidine-2,6-dione hydrogen chloride (5.2 g, 32 mmol),imidazole (4.7 g, 70 mmol) and triphenyl phosphite (9.9 mL, 38 mmol) andheated to reflux for 22 hours. To the mixture, was added water (100 mL).The suspension was filtered and washed with water (2×100 mL), ethylacetate (2×100 mL), sodium hydrogen carbonate (sat, 100 mL) and water(100 mL) to give a white solid, which was stirred in DMF (40 mL)overnight. The suspension was filtered and washed with DMF (5 mL) togive a white solid. The solid was stirred in water (100 mL) at 60° C.for 2 hours, then at room temperature overnight. The suspension wasfiltered and washed with water (2×50 mL) to give3-(2,6-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as awhite solid (3.4 g, 38% yield): HPLC: Waters Symmetry C₁₈, 5 μm, 3.9×150mm, 1 mL/min, 240 nm, 20/80 CH₃CN/0.1% H₃PO₄, 5.37 min (99.8%); mp:270-272° C.; ¹H NMR (DMSO-d₆) δ 2.10-2.22 (m, 1H, CHH), 2.43 (s, 3H,CH₃), 2.56-2.72 (m, 5H, CH₃, 2CHH), 2.76-2.92 (m, 1H, CHH), 5.24 (dd,J=6, 11 Hz, 1H, NCH), 7.52 (d, J=8 Hz, 1H, Ar), 7.64 (dd, J=2, 8 Hz, 1H,Ar), 7.82 (s, 1H, Ar), 11.02 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 20.76,20.95, 23.34, 30.60, 56.47, 120.05, 125.20, 126.39, 135.96, 136.19,144.87, 153.99, 160.40, 169.53, 172.62; LCMS: MH=286; Anal Calcd forC₁₅H₁₅N₃O₃+2H₂O: C, 56.07; H, 5.96; N, 13.08. Found: C, 55.73; H, 5.75;N, 13.01.

5.22-BENZYLOXY-N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-6-YL]-ACETAMIDE

Step 1: To a stirred mixture of 5-amino-isatoic anhydride (1.0 g, 5.6mmol) and triethyl amine (0.8 mL, 9.0 mmol) in acetronitrile (15 mL),was added benzyloxyacetyl chloride (0.87 mL, 5.6 mmol) dropwise at roomtemperature. The mixture was kept at room temperature overnight. To themixture, was added triethylamine (3.1 mL, 22 mmol),3-amino-piperidine-2,6-dione hydrogen chloride (0.92 g, 5.6 mmol), andacetic acid (3.2 mL, 56 mmol). The mixture was heated at 80° C. for 8hours. To the mixture, was added water (75 mL). The suspension wasfiltered and washed with water (75 mL) and ethyl acetate (75 mL) to givea dark solid, which was purified with column chromatography (Silica Gel,methanol/methylene chloride 0% to 10% in 15 min) to give2-amino-5-(2-benzyloxy-acetylamino)-N-(2,6-dioxo-piperidin-3-yl)-benzamideas a white solid (0.28 g, 12% yield): ¹H NMR (DMSO-d₆) δ 1.92-2.18 (m,2H, 2CHH), 2.50-2.55 (m, 1H, CHH), 2.72-2.84 (m, 1H, CHH), 4.03 (s, 2H,CH₂), 4.61 (s, 2H, CH₂), 4.68-4.77 (m, 1H, NCH), 6.19 (br, 2H, NH₂),6.68 (d, J=9 Hz, 1H, Ar), 7.30-7.42 (m, 6H, Ar), 7.62 (d, J=2 Hz, 1H,Ar), 8.43 (d, J=8 Hz, 1H, NH), 9.44 (s, 1H, NH), 10.84 (s, 1H, NH); ¹³CNMR (DMSO-d₆) δ 24.09, 30.96, 49.12, 69.37, 72.35, 114.27, 116.23,121.11, 125.99, 126.13, 127.64, 127.77, 128.27, 137.68, 146.19, 167.28,168.36, 172.35, 173.01.

Step 2: A solution of2-amino-5-(2-benzyloxy-acetylamino)-N-(2,6-dioxo-piperidin-3-yl)-benzamide(0.26 g, 0.6 mmol) and trimethyl orthoformate (2 mL) and p-toluenesulfonic acid (60 mg) in acetonotrile (10 mL) was heated to reflux for21 hours. To the mixture, was added water (25 mL) and ether (25 mL). Thesuspension was filtered and washed with water (50 mL) and ethyl acetate(50 mL) to give2-benzyloxy-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-yl]-acetamideas a white solid (180 mg, 72% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH₃CN/0.1% H₃PO₄, 2.87 min (99.3%);mp: 248-250° C.; ¹H NMR (DMSO-d₆) δ 2.14-2.16 (m, 1H, CHH), 2.62-2.87(m, 3H, CH₂, CHH), 4.15 (s, 2H, CH₂), 4.64 (s, 2H, CH₂), 5.49-5.50 (m,1H, NCH), 7.31-7.41 (m, 5H, Ar), 7.68 (d, J=9 Hz, 1H, Ar), 8.06-8.10 (m,1H, NH), 8.28 (s, 1H, CH), 8.55 (br, 1H, Ar), 10.24 (s, 1H, NH), 11.16(s, 1H, NH); ¹¹C NMR (DMSO-d₆) δ 23.05, 31.48, 58 (br), 69.87, 72.92,115.69, 122.15, 127.30, 128.16, 128.28, 128.34, 128.77, 137.98, 138.14,144.06, 146.48, 160.10, 168.93, 170.43, 172.90; LCMS: MH=421; Anal Calcdfor C₂₂H₂₀N₄O₅: C, 62.85; H, 4.79; N, 13.33. Found: C, 60.60; H, 4.29;N, 12.54.

5.3 3-(6-FLUORO-2-METHYL-4-OXO-4,1-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

To a stirred mixture of 2-amino-5-fluorobenzoic acid (1.2 g, 7.8 mmol)and imidazole (0.63 g, 9.3 mmol) in acetonitrile (15 mL), was addedacetyl chloride (0.66 mL, 9.3 mmol) at room temperature. The mixture wasstirred at room temperature overnight. To the mixture, was added3-amino-piperidine-2,6-dione hydrogen chloride (1.3 g, 7.7 mmol),imidazole (1.2 g, 17 mmol) and triphenyl phosphite (2.2 mL, 8.5 mmol)and heated to reflux for 22 hours. The suspension was filtered andwashed with water (2×50 mL), ethyl acetate (2×50 mL), and water (50 mL)to give3-(6-fluoro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as awhite solid (1.2 g, 53% yield): HPLC: Waters Symmetry C₁₈, 5 μm, 3.9×150mm, 1 mL/min. 240 nm, 20/80 CH₃CN/0.1% H₃PO₄, 5.99 min (99.3%); mp:273-275° C.; ¹H NMR (DMSO-d₆) δ 2.13-2.23 (m, 1H, CHH), 2.57-2.71 (m,5H, CH₃, 2CHH), 2.75-2.95 (m, 1H, CHH), 5.30 (dd, J=6, 11 Hz, 1H, NCH),7.70-7.73 (m, 3H, Ar), 11.06 (s, 1H. NH); ¹³C NMR (DMSO-d₆) δ 20.82,23.31, 30.58, 56.63, 110.54 (d, J_(C-F)=23 Hz), 121.40 (d, J_(C-F)=8Hz), 123.24 (d, J_(C-F)=24 Hz), 129.47 (d, J_(C-F)=8 Hz), 143.75,154.45, 159.83 (d. J_(C-F)=245 Hz), 159.86 (d, J_(C-F)=3 Hz), 169.37,172.58; LCMS: MH=290; Anal Calcd for C₁₄H₁₂N₃O₃F 1.3H₂O: C, 53.78; H,4.71; N, 13.44. Found: C, 53.75; H, 4.61; N, 13.50.

5.4 3-(6-CHLORO-2-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

To a stirred mixture of 2-amino-5-chlorobenzoic acid (2.0 g, 12 mmol)and imidazole (1.0 g, 14 mmol) in acetonitrile (30 mL), was added acetylchloride (1.0 mL, 14 mmol) at room temperature. The mixture was stirredat room temperature overnight. To the mixture, was added3-amino-piperidine-2,6-dione hydrogen chloride (1.9 g, 12 mmol),imidazole (1.8 g, 26 mmol) and triphenyl phosphite (3.7 mL, 26 mmol) andheated to reflux for 22 hours. To the mixture, was added water (60 mL).The suspension was filtered and washed with water (2×50 mL), ethylacetate (2×50 mL), and water (50 mL) to give3-(6-chloro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as awhite solid (2.9 g, 80% yield): HPLC: Waters Symmetry C₁₈, 5 μm, 3.9×150mm, 1 mL/min, 240 nm, 25/75 CH₃CN/0.1% F₃PO₄, 6.65 min (98.5%); 276-278°C.; ¹H NMR (DMSO-d₆) δ 2.15-2.24 (m, 1H, CHH), 2.58-2.71 (m, 5H, CH₃,2CHH), 2.78-2.92 (m, 1H, CHH), 5.30 (dd, J=6, 11 Hz, 1H, NCH), 7.66 (d,J=9 Hz, 2H, Ar), 7.85 (dd, J=3, 9 Hz, 1H, Ar), 7.98 (d, J=2 Hz, 1H, Ar),11.06 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 20.79, 23.45, 30.57, 56.71,121.47, 124.89, 128.89, 130.77, 134.87, 145.57, 155.67, 159.53, 169.31,172.56; LCMS: MH=306, 308; Anal Calcd for C₁₄H₁₂N₃O₃Cl+2H₂O: C, 49.20;H, 4.72; N, 12.30; Cl, 10.37. Found: C, 49.34; H, 4.57; N, 12.20; Cl,10.39.

5.5 3-(6-BROMO-2-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

Step 1: A stirred mixture of 5-bromo-isatoic anhydride (6.0 g, 25 mmol),3-amino-piperidine-2,6-dione hydrogen chloride (4.1 g, 25 mmol),triethylamine (18 mL, 129 mmol), and acetic acid (15 mL, 262 mmol) inacetonitrile (60 mL) was heated at 90° C. for 18 hours. The suspensionwas filtered and washed with acetonitrile (2×80 mL), water (2×80 mL) andethyl acetate (2×80 mL) to give2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-bromo-benzamide as a white solid(5.8 g, 72% yield): LCMS: MH=326, 328. The sample was used in the nextstep without further purification.

Step 2: A solution of2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-bromo-benzamide (1.0 g, 3 mmol)and trimethyl orthoacetate (1.6 mL) and p-toluene sulfonic acid (250 mg)in acetonotrile (10 mL) was heated to reflux for 7 days. The suspensionwas filtered and washed with ethyl acetate (10 mL), methanol (5 mL) andethyl acetate (10 mL) to give3-(6-bromo-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as anoff-white solid (108 mg, 10% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH₃CN/0.1% F₃PO₄, 5.17 min (98.7%);mp: 273-275° C.; ¹H NMR (DMSO-d₆) δ 2.14-2.27 (m, 1H, CHH), 2.56-2.69(m, 2H, 2CHH), 2.64 (s, 3H, CH₃), 2.72-2.90 (m, 1H, CHH), 5.29 (dd. J=6,11 Hz, 1H, NCH), 7.58 (d, J=9 Hz, 1H, Ar), 7.98 (dd, J=2, 9 Hz, 1H, Ar),8.12 (d, J=2 Hz, 1H, Ar), 11.06 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 20.72,23.42, 30.50, 56.64, 118.80, 121.77, 127.94, 128.95, 137.51, 145.76,155.74, 159.32, 167.24, 172.49; LCMS: MH=350, 352; Anal Calcd forC₁₄H₁₂N₃O₃Br: C, 48.02; H, 3.45; N, 12.00. Found: C, 48.02; H, 3.18; N,11.76.

5.6 3-(6-HYDROXY-2-METHYL-4-OXO-4H-QUINOLIN-3-YL)-PIPERIDINE-2,6-DIONE

To a stirred mixture of 2-amino-5-hydroxy benzoic acid (5.1 g, 33 mmol)and imidazole (5.0 g, 73 mmol) in acetonitrile (60 mL), was added acetylchloride (5.2 mL, 73 mmol) at room temperature. The mixture was stirredat room temperature overnight. To the mixture, was added3-amino-piperidine-2,6-dione hydrogen chloride (6.0 g, 37 mmol),imidazole (5.0 g, 73 mmol) and triphenyl phosphite (10.5 mL, 40 mmol)and heated to reflux for 22 hours. To the mixture, was added water (100mL) and conc HCl until pH 1. The solvent was removed in vacuo. To theresidue, was added water (50 mL). The aqueous layer was extracted withethyl acetate (50 mL). To the aqueous layer, was added ethyl acetate (50mL), and the mixture was stirred at room temperature to give asuspension. The suspension was filtered to give a solid, which wasstirred in methanol (50 mL) overnight. The suspension was filtered andwashed with methanol (2×30 mL) and water to give3-(6-hydroxy-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione asan off-white solid (2.97 g, 31% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 5/95 grad 95/5 in 5 min CH₃CN/0.1% H₃PO₄,4.50 min (96.8%); mp: 315-317° C.; ¹H NMR (DMSO-d₆) δ 2.13-2.18 (m, 1H,CHH), 2.58 (s, 3H, CH₃), 2.62-2.71 (m, 2H, 2CHH), 2.78-2.91 (m, 1H,CHH), 5.22 (dd, J=6, 11 Hz, 1H, NCH), 7.24-7.32 (m, 2H, Ar), 7.49 (d.J=9 Hz, 1H, Ar), 10.07 (s, 1H, OH), 11.00 (s, 1H, NH); ¹³C NMR (DMSO-d₆)δ 20.97, 23.10, 30.59, 56.36, 108.59, 121.24, 124.13, 128.19, 140.14,151.39, 155.89, 160.24, 169.58, 172.63; LCMS: MH=288; Anal Calcd forC₁₄H₁₃N₃O₄+1H₂O: C, 55.08; H, 4.95; N, 13.76. Found: C, 54.82; H, 4.74;N, 13.54.

5.7 3-(6-CHLORO-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

Step 1: A stirred mixture of 5-chloroisatoic anhydride (0.51 g, 2.5mmol), 3-amino-piperidine-2,6-dione hydrogen chloride (0.42 g, 2.5mmol), triethylamine (1.8 mL, 12.7 mmol), and acetic acid (1.5 mL, 25.3mmol) in acetonitrile (5 mL) was heated at 150° C. in a microwave ovenfor 5 miutes. The suspension was filtered and washed with water (50 mL)and ethyl acetate (20 mL) to give2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-chloro-benzamide as a white solid(0.31 g, 42% yield): ¹H NMR (DMSO-d₆) δ 1.91-2.12 (m, 2H, 2CHH),2.50-2.56 (m, 1H, CHH), 2.72-2.80 (m, 1H, CHH), 4.71-4.76 (m, 1H, NCH),6.58 (brs, 2H, NH₂), 6.74 (d, J=8 Hz, 1H, Ar), 7.19 (dd, J=2, 9 Hz, 1H,Ar), 7.58 (t; J=2 Hz, 1H, Ar), 8.62 (d, J=8 Hz, 1H, NH), 10.86 (s, 1H,NH); ¹³C NMR (DMSO-d₆) δ 23.99, 30.89, 49.00, 114.62, 117.60, 118.04,127.25, 131.63, 148.61, 167.37, 172.20, 172.93; LCMS: MH=282, 284.

Step 2: A solution of2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-chloro-benzamide (0.31 g, 1.1mmol) and trimethyl orthoformate (4 mL) and p-toluene sulfonic acid (50mg) was heated to 150° C. in a microwave oven for 10 minutes. Thesuspension was filtered and washed with ethyl acetate (10 mL), methanol(5 mL) and ethyl acetate (10 mL) to give3-(6-chloro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a whitesolid (230 mg, 74% yield): HPLC: Waters Symmetry C₁₈, 5 μm, 3.9×150 mm,1 mL/min, 240 nm, 30/70 CH₃CN/0.1% H₃PO₄, 4.01 min (100%); mp: 302-305°C.; ¹H NMR (DMSO-d₆) δ 2.13-2.20 (m, 1H, CHH), 2.62-2.93 (m, 3H, CH₂,CHH), 5.52 (br, 1H, NCH), 7.76 (d, J=9 Hz, 1H, Ar), 7.91 (dd, J=2, 9 Hz,1H, Ar), 8.10 (d, J=2 Hz, 1H, Ar), 8.41 (s, 1H, CH), 11.19 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 22.39, 30.87, 56.29 (br), 122.56, 125.05, 129.47,131.59, 134.82, 146.19, 147.75, 158.73, 169.68, 172.39; LCMS: MH=292,294; Anal Calcd for C₁₃H₁₀N₃O₃Cl: C, 53.53; H, 3.46; N, 14.41. Found: C,53.43; H, 3.21; N, 14.27.

5.8 3-(6-BROMO-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

Step 1: A stirred mixture of 5-bormo-isatoic anhydride (6.0 g, 25 mmol),3-amino-piperidine-2,6-dione hydrogen chloride (4.1 g, 25 mmol),triethylamine (18 mL, 129 mmol), and acetic acid (15 mL, 262 mmol) inacetonitrile (60 mL) was heated at 90° C. for 18 hours. The suspensionwas filtered and washed with acetonitrile (2×80 mL), water (2×80 mL) andethyl acetate (2×80 mL) to give2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-bromo-benzamide as a white solid(5.8 g, 72% yield): LCMS: MH=326, 328. The sample was used in the nextstep without further purification.

Step 2: A solution of2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-bromo-benzamide (0.51 g, 1.5mmol) and trimethyl orthoformate (2 mL) and p-toluene sulfonic acid (150mg) in acetonitrile (10 mL) was heated to reflux for 12 hours. To themixture, was added water (70 mL), and stirred at room temperature for 2hours. The suspension was filtered and washed with ethyl acetate (10mL). The solid in NMP (3 mL) was heated at 80° C. To the solution, wasadded water (1.5 mL), and the mixture was allowed to cool to roomtemperature. The suspension was filtered and washed with NMP (1 mL) andethyl acetate (10 mL) to give3-(6-bromo-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a whitesolid (350 mg, 68% yield): HPLC: Waters Symmetry C₁₈, 5 μm, 3.9×150 mm,1 mL/min, 240 nm, 30/70 CH₃CN/0.1% H₂PO₄, 4.18 min (99.9%); mp: 312-314°C.; ¹H NMR (DMSO-d₆) δ 2.14-2.21 (m, 1H, CHH), 2.60-2.74 (m, 2H, 2CHH),2.83-2.93 (m, 1H, CHH), 5.51 (brs, 1H, NCH), 7.68 (d, J=9 Hz, 1H, Ar),8.03 (dd, J=2, 9 Hz, 1H, Ar), 8.24 (d, J=2 Hz, 1H, Ar), 8.42 (5, 1H,CH), 11.19 (s, 1H, NH); NMR (DMSO-d₆) δ 22.45, 30.93, 55.49, 119.83,122.96, 128.23, 129.65, 137.61, 146.52, 147.94, 158.66, 169.75, 172.46;LCMS: MH=336, 338; Anal Calcd for C₁₃H₁₀N₃O₁Br+0.3H₂O: C, 45.72; H,3.13; N, 12.30; Br, 23.39. Found: C, 45.46; H, 2.75; N, 12.15; Br,22.81.

5.9 3-(6-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-D ONE

Step 1: A mixture of 2-amino-5-methylbenzoic acid (1.0 g, 6.6 mmol) andCDI (1.0 g, 6.1 mmol) in acetonitrile (15 mL) was stirred at roomtemperature for 1.5 hours. To the suspension, was added3-amino-piperidine-2,6-dione hydrogen chloride (1.0 g, 6.1 mmol) andsodium hydrogen carbonate (0.45 g, 3.6 mmol), and the mixture was heatedat 50° C. for 21 hours. The suspension was cooled to room temperaturefor 1 hour. The suspension was filtered and washed with acetonitrile (20mL), water (2×20 mL) and ethyl acetate (20 mL) to give2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-methyl-benzamide as a blue solid(1.1 g, 63% yield): ¹H NMR (DMSO-d₆) δ 1.91-1.98 (m, 1H, CHH), 2.05-2.14(m, 1H, CHH), 2.17 (s, 3H, CH₃), 2.50-2.56 (m, 1H, CHH), 2.73-2.85 (m,1H, CHH), 4.69-4.77 (m, 1H, NCH), 6.20 (br, 2H, NH₂), 6.63 (d, J=9 Hz,1H, Ar), 7.00 (dd, J=2, 8 Hz, 1H, Ar), 7.34 (d, J=2 Hz, 1H, Ar), 8.43(d, J=8 Hz, 1H, NH), 10.84 (s, 111, NH); ¹³C NMR (DMSO-d₆) δ 19.89,24.13, 30.92, 48.93, 113.87, 116.48, 122.81, 127.87, 132.72, 147.40,168.55, 172.40, 172.97.

Step 2: A solution of2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-methyl-benzamide (0.45 g, 1.7mmol) and trimethyl orthoformate (4 mL) and p-toluene sulfonic acid (80mg) was heated to 160° C. in a microwave oven for 8 minutes. To thesuspension, was added methanol (20 mL), methylene chloride (20 mL), andCelite (5 mL). The solvent was removed in vacuo. The reside was placedin a SIM and was purified with column chromatography (Silca Gel,methanol/methylene chloride 0% gradient 10% in 15 min) to give as3-(6-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a bluesolid (50 mg, 9% yield): HPLC: Waters Symmetry C₁₈, 5 μm, 3.9×150 mm, 1mL/min, 240 nm, 30/70 CH₃CN/0.1% H₃PO₄, 2.78 min (96.1%); mp: 285-287°C.; ¹H NMR (DMSO-d₆) δ 2.11-2.18 (m, 1H, CHH), 2.46 (s, 3H, CH₃),2.56-2.74 (m, 2H, 2CHH), 2.82-2.93 (m, 1H, CHH), 5.48 (br, 1H, NCH),7.61 (d, J=8 Hz, 1H, Ar), 7.70 (dd. J=2, 8 Hz 1H, Ar), 7.94 (br, 1H,Ar), 8.33 (s, 1H, CH), 11.15 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 20.72,22.51, 30.91, 57.00 (br), 121.09, 125.38, 127.00, 135.89, 137.07,145.46, 146.45, 159.60, 169.88, 172.44; LCMS: MH=272; Anal Calcd forC₁₄H₁₃N₃O₃: C, 61.99; H, 4.83; N, 15.49. Found: C, 61.78; H, 4.57; N,15.34.

5.10 3-(6-AMINO-2-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

Step 1: To a stirred mixture of 2-amino-5-nitrobenzoic acid (5.0 g, 28mmol) and imidazole (2.2 g, 33 mmol) in acetonitrile (50 mL), was addedacetyl chloride (2.3 mL, 33 mmol) at room temperature. The mixture wasstirred at room temperature overnight. To the mixture, was added3-amino-piperidine-2,6-dione hydrogen chloride (4.5 g, 28 mmol),imidazole (4.1 g, 60 mmol) and triphenyl phosphite (8.7 mL, 33 mmol) andheated to reflux for 22 hours. To the mixture, was added water (60 mL).The suspension was filtered and washed with water (2×50 mL), ethylacetate (2×50 mL), and water (50 mL) to give3-(2-methyl-6-nitro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as anoff-white solid (5.3 g, 61% yield): ¹H NMR (DMSO-d₆) δ 2.19-2.26 (m, 1H,CHH), 2.60-2.69 (m, 2H, 2CHH), 2.72 (s, 3H, CH₁), 2.79-2.87 (m, 1H,CHH), 5.37 (dd, J=5, 11 Hz, 1H, NCH), 7.83 (d, J=9 Hz, 1H, Ar), 8.56(dd, J=3, 9 Hz, 1H, Ar), 8.74 (dt, J=3 Hz 1H, Ar), 11.12 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 20.69, 23.82, 30.57, 56.98, 119.46, 120.20, 122.21,128.45, 128.74, 144.90, 150.85, 159.13, 159.78, 169.12, 172.53.

Step 2: A suspension of3-(2-methyl-6-nitro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (4.1g, 13 mmol) and 20% Pd(OH)₂/C (0.9 g) in cyclohexene (20 mL) and DMF (60mL) was heated in a 125° C. oil bath overnight. The suspension wasfiltered thru a pad of Celite, and washed with DMF (30 mL). The DMFsolution and Charcoal (4 g) were stirred at room temperature for 5hours. The suspension was filtered thru a pad of Celite. The solvent wasremoved in vacuo. To the residue, was added DMF (20 mL), and then water(80 mL) to give a suspension. The suspension was filtered and washedwith water (50 mL), ethyl acetate (50 mL) and water (50 mL) to give abrown solid, which was purified with preparative HPLC (C18 5/95 for 2minutes then gradient to 50/50 in 18 min CH₃CN/H₂O) to give3-(6-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as awhite solid (1.15 g, 31% yield): HPLC: Waters Xterra C₁₈, 5 μm, 3.9×150mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% NH4HCO2, 5.31 min (99.8%); mp:314-316° C.; ¹H NMR (DMSO-d₆) δ 2.08-2.14 (m, 1H, CHH), 2.54 (s, 3H,CHO, 2.55-2.67 (m, 2H, 2CHH), 2.75-2.90 (m, 1H, CHH), 5.16 (dd. J=5, 11Hz, 1H, NCH), 5.59 (brs, 2H, NH₂), 7.04-7.08 (m, 2H, Ar), 7.31-7.34 (m,1H, Ar), 10.97 (s, 1H, NH); NMR (DMSO-d₆) δ 21.06, 22.96, 30.62, 56.22,105.89, 121.34, 122.61, 127.35, 137.89, 147.63, 149.24, 160.39, 169.68,172.66; LCMS: MH=287; Anal Calcd for C₁₄H₁₄N₄O₃+1H₂O: C, 55.26; H, 5.30;N, 18.41. Found: C, 54.99; H, 5.22; N, 18.35.

5.11[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-6-YLMETHYL]-CARBAMICACID TERT-BUTYL ESTER

Step 1: A mixture of 5-methyl-2-nitro-benzoic acid methyl ester (93.95g, 481.35 mmol), 1,3-dibromo-5,5-dimethylhydantoin (75.70 g, 264.74mmol), in methyl acetate (550 mL) was heated at 78° C. for 40 minuteswhile stirred with a mechanical stirrer. Then a solution of2,2′-azobisisobutyro-nitrile (3.95 g, 24.07 mmol) in methyl acetate (80mL) was added, and the mixture was heated at about 75° C. for 13 hours.The mixture was allowed to cooled to 15° C. and stirred for 2 hours toage the precipitate. The suspension was filtered, washed with 10° C.methyl acetate (2×50 mL) to give a brown filtrate. To the filtrate, wasadded heptane (500 mL). The organic layer was washed with 2% brine(2×500 mL) and water (2×500 mL), and concentrated to about 2 volumes. Tothe mixture, was added t-butyl methyl ether (or MTBE, 300 mL). Themixture was heated at about 70° C. for 15 minutes, cooled to about 53°C. over one hour, seeded with the product (about 250 mg, or simplyre-crystallized) at 45° C., then at 20˜25° C., while blowing nitrogenwith a glass pipette overnight. The resulting solid was filtered via amedium pore-sized funnel, washed with a pre-cooled 10° C. mixed solventof heptane/MTBE (1/2 vol/vol) and suction dried in hood overnight togive 5-bromomethyl-2-nitro-benzoic acid methyl ester as an off-whitesolid (58.3 g, 44.0% yield). The solid was used in the next step withoutfurther purification.

Step 2: A stirred mixture of 5-bromomethyl-2-nitro-benzoic acid methylester (50.5 g, 184 mmol), di-tert-butyl iminodicarboxylate (40.15 g, 185mmol), cesium carbonate (123.1 g, 377.7 mmol), and lithium iodide (1.23g, 9.21 mmol) in 2-butanone (556 mL) was heated to reflux in a 100° C.oil bath for 12 hours while stirred with a mechanical stirrer. Themixture was allowed to cool to room temperature. To the mixture, wasadded brine (300 mL), water (300 mL), and ethyl acetate (750 mL), andthe mixture was stirred for 10 minutes. The suspension was filteredthrough a pad of Celite. The two layers were separated, and the organiclayer was evaporated to a less volume. The aqueous layer was extractedwith ethyl acetate (2×150 mL). The combined organic layers were washedwith brine (500 mL), dried over magnesium sulfate while de-colored atthe same time by charcoal at room temp with stirring for 30 minutes. Theblack mixture was filtered through a pad of Celite. The filtrate wasevaporated to give5-(di-tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid methyl esteras a brown oil (74.18 g, 98% yield). The product was used in the nextstep without further purification.

Step 3: To a stirred brown solution of5-(di-tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid methyl ester(74.18 g, 180.7 mmol) in methylene chloride (700 mL) was addedtrifluoroacetic acid (26.2 mL, 352.4 mmol), and the mixture was stirredat room temp overnight. Sat. sodium bicarbonate (400 mL) was added tothe solution, and the mixture was stirred for 10 minutes. The organiclayer was separated, dried over magnesium sulfate, and evaporated togive 5-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid methylester as a brown oil (52.5 g, 94% crude yield). The product was used inthe next step without further purification.

Step 4: A mixture of 5-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoicacid methyl ester (52.5 g, 169.3 mmol), lithium hydroxide (4.86 g, 203.1mmol) in methanol (546 mL) and water (273 mL) was stirred with amechanical stirrer at room temp overnight. The methanol was evaporated,and to the aqueous solution, was added 1 N HCl (270 mL) to form theprecipitate. Ether (350 mL) was added, and the mixture was stirred at 0°C. for 2 hours. The mixture was evaporated. To the residue, was addedwater (500 mL). The aqueous layer was extracted with methylene chloride(3×100 mL). The combined organic layers were separated, dried overmagnesium sulfate, and concentrated to give5-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid as a brown oil(21.0 g, 41% yield). The product was used in the next step withoutfurther purification.

Step 5: A mixture of 5-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoicacid (21.0 g, 70.9 mmol) in methanol (210 mL) and palladium/carbon (2 g)was hydrogenated with a Parr-shaker overnight at 51 psi. The blackmixture was filtered through a pad of Celite, and the filtrate wasevaporated to give a brown oil, which was stirred in ether (300 mL)overnight. The ether slurry was filtered to give2-amino-5-(tert-butoxycarbonylamino-methyl)-benzoic acid as a brownsolid (9.3 g, 49% yield). The product was used in the next step withoutfurther purification.

Step 6: To a stirred solution of2-amino-5-(tert-butoxycarbonylamino-methyl)-benzoic acid (9.3 g, 34.9mmol), imidazole (2.85 g, 41.9 mmol) in acetonitrile (120 mL), was addedacetyl chloride (3.0 mL, 41.9 mmol) and stirred at room temp overnight.Then to the mixture, was added 3-amino-piperidine-2,6-dione hydrogenchloride (5.74 g, 34.9 mmol), imidazole (4.76 g, 69.8 mmol) andtriphenyl phosphite (11.0 mL, 41.9 mmol), and the mixture was heated toreflux for 6 hours. The mixture was allowed to cool to room temperature,and water (about 400 mL) was added. The suspension was filtered, washedwith water (50 mL), ethyl acetate (20 mL), ether (50 mL), and suctiondried to give[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-carbamicacid tert-butyl ester as an off-white solid (9.7 g, 70% yield): HPLC,Waters Symmetry C₁₈, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90CH₃CN/0.1% H₃PO₄, grad. to 95/5 in 5 min. kept 5 min, 5.95 min (96.7%);mp, 212.5-214.5° C.; ¹H NMR (DMSO-d₆) δ 1.40 (s, 9H, CMe₃), 2.15-2.18(m, 1H, CHH), 2.57-2.86 (m, 6H, CHCH₂, CH₃), 4.23 (d, J=6 Hz, 2H,CH₂NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.52 (t, J=6 Hz, 1H, CH₂NH),7.56-7.88 (m, 3H, Ar), 11.03 (s, 1H, NH); NMR (DMSO-d₆) δ 20.92, 23.40,28.20, 30.62, 42.97, 56.52, 77.94, 119.98, 123.50, 126.51, 133.74,138.76, 145.75, 154.52, 155.79, 160.44, 169.47, 172.61. LCMS MH=401;Anal Calcd For C₂₀H₂₄N₄O₅: C, 59.99: H, 6.04; N, 13.99. Found: C, 59.83;H, 5.98; N, 13.85.

5.123-(6-AMINOMETHYL-2-METHYL-1-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONEHYDROGENCHLORIDE

Step 1: To a stirred brown solution of[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-carbamicacid tert-butyl ester (3.5 g, 8.7 mmol) in methanol (36 mL) andmethylene chloride (36 mL), was added 2 M HCl in ether (102 mL), and themixture was stirred overnight. The solvent was evaporated, and theresidue was stirred in ether (100 mL) for 2 hours. The suspension wasfiltered to give3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride as a light yellow solid (3.2 g, 109% crude yield). Theproduct was used in the next step without further purification.

Step 2:3-(6-Aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.95 g) was dissolved in water (100 mL). The solutionwas washed with ethyl acetate (2×100 mL). The aqueous layer wasevaporated to give3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride as an off-white solid (0.79 g, 84% yield); HPLC,Waters Xterra RP 18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, Waters LCModule 1, 05/95 CH₃CN/0.1% (HCO₂)NH₄ is ° C.rat, 4.67 min (98.5%); mp,299-301° C.; ¹HNMR (DMSO-d₆) δ 2.18-2.24 (m, 1H, CHH), 2.59-2.89 (m, 6H,CHCH₂, CH₃), 4.14-4.19 (m, 2H. ArCH₂), 5.34 (dd, J=5, 11 Hz, 1H, CH),7.71-8.20 (m, 3H, Ar), 8.54 (brs, 3H, ClNH₃), 11.08 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 20.86, 22.97, 30.60, 41.61, 56.75, 119.85, 125.75, 126.83,132.81, 135.80, 145.35, 156.51, 159.96, 169.23, 172.59. LCMS MH=301;Anal Calcd For C₁₅H₁₇N₄O₃Cl+1.0H₂O and +0.8HCl: C, 46.92; H, 5.20; N,14.59; Cl, 16.62. Found: C, 46.72; H, 5.15; N, 14.29; Cl, 16.59.

5.13 HEPTANOIC ACID[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-6-YLMETHYL]-AMIDE

To a stirred suspension of3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.49 g, 1.5 mmol) in acetonitrile (10 mL), was addedheptanoyl chloride (0.34 mL, 2.2 mmol) and N,N-diisopropyl ethylamine(0.60 mL, 3.7 mmol). The mixture was stirred at room temp for one hour.The solvent was evaporated, and the residue was purified by flash columnchromatography (Silica gel, methanol/methylene chloride 4%/96%) to giveheptanoic acid[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-amideas an off-white solid (349 mg, 58% yield); HPLC, Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, gradient to95/5 in 5 min, kept for 5 min, 6.12 min (96.3%); mp, 223-225° C.; ¹HNMR(DMSO-d₆) δ 0.84 (t, J=6 Hz, 3H, CH₃ of long chain), 1.24-2.20 (m, 11H,CH₂CH₂CH₂CH₂CH₂, CHH), 2.57-2.86 (m, 6H, CHCH₂, CH₃), 4.36 (d, J=6 Hz,2H, CH₂NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.56-7.88 (m, 3H, Ar), 8.41(t, J=6 Hz, 1H, CH₂NH), 11.03 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 13.86,20.92, 21.95, 23.39, 25.23, 28.31, 30.61, 30.99, 35.33, 41.57, 56.51,119.99, 123.79, 126.51, 133.96, 138.38, 145.74, 154.53, 160.40, 169.47,172.25, 172.60. LCMS MH=413; Anal Calcd For C₂₂H₂₈N₄O₄: C, 64.06; H,6.84; N, 13.58. Found: C, 63.76; H, 6.68; N, 13.42.

5.14 CYCLOPROPANECARBOXYLIC ACID[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-6-YLMETHYL]-AMIDE

To a stirred suspension of3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.51 g, 1.5 mmol) in acetonitrile (10 mL), was addedcyclopropanecarbonyl chloride (0.21 mL, 2.3 mmol) and N,N-diisopropylethylamine (0.62 mL, 3.8 mmol). The mixture was stirred at roomtemperature for one hour. The solvent was evaporated, and the residuewas purified by flash column chromatography (Silica gel,methanol/methylene chloride 4%/96%) to give cyclopropanecarboxylic acid[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-amideas an off-white solid (233 mg, 42% yield); HPLC, Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, gradient to95/5 in 5 min, kept for 5 min, 5.01 min (98.4%); mp, 281-283° C.; ¹HNMR(DMSO-d₆) δ 0.64-0.74 (m, 4H, CH₂CH₂ of cyclopropane ring), 1.57-1.66(m, 1H, CH of cyclopropane ring), 2.15-2.21 (m, 1H, CH), 2.57-2.89 (m,6H, CHCH₂, CH₃), 4.39 (d, J=5 Hz, 2H, CH₂NH), 5.26 (dd, J=6, 11 Hz, 1H,CH), 7.57-7.89 (m, 3H, Ar), 8.68 (t, J=6 Hz, 1H, CH₂NH), 11.03 (s, 1H,NH); ¹³C NMR (DMSO-d₆) δ 6.31, 13.55, 20.93, 23.40, 30.61, 41.77, 56.53,120.01, 123.78, 126.58, 134.02, 138.34, 145.78, 154.55, 160.44, 169.47,172.62, 172.70. LCMS MH=413; Anal Calcd For C₁₉H₂₀N₄O₄: C, 61.95; H,5.47; N, 15.21. Found: C, 61.86; H, 5.49; N, 15.04.

5.153-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-6-YLMETHYL]-1,1-DIMETHYL-UREA

To a stirred suspension of3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.50 g, 1.5 mmol) in acetonitrile (10 mL), was addeddimethyl carbamyl chloride (0.21 mL, 2.2 mmol) and N,N-diisopropylethylamine (0.62 mL, 3.8 mmol). The mixture was stirred at roomtemperature overnight. The solvent was evaporated, and the residue waspurified by flash column chromatography (Silica gel, methanol/methylenechloride 4%/96%) to give3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-1,1-dimethyl-ureaas an off-white solid (290 mg, 52% yield); HPLC, Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 mL/min, 240 nm, 10190 CH₃CN/0.1% H₃PO₄, gradient to95/5 in 5 min, kept for 5 min, 4.66 min (98.7%); mp, 264-268° C.; ¹HNMR(DMSO-d₆) δ 2.14-2.20 (m, 1H, CH), 2.56-2.86 (m, 12H, N(CH₃)₂, CHCH₂,CH₃), 4.31 (d, J=5 Hz, 2H, CH₂NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.00(t, J=5 Hz, 1H, CH₂NH), 7.54-7.89 (m, 3H, Ar), 11.03 (s, 1H. NH); ¹³CNMR (DMSO-d₆) δ 20.95, 23.38, 30.61, 35.85, 43.20, 56.49, 119.88,123.54, 126.30, 133.91, 139.98, 145.59, 154.27, 158.09, 160.50, 169.49,172.62. LCMS MH=372; Anal Calcd For C₁₈H₂₁N₅O₄+0.5H₂O: C, 56.83; H,5.83; N, 18.41. Found: C, 56.71; H, 5.81; N, 18.18.

5.16 2-(4-CHLORO-PHENYL)-N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-6-YLMETHYL]-ACETAMIDE

To a stirred solution of (4-chloro-phenyl)-acetic acid (0.30 g, 1.8mmol) in DMF (8 mL) in a 40° C. oil bath, was added 1,1′carbonyldiimidazole (0.31 g, 1.9 mmol), and the mixture was stirred forone hour. Then3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.59 g, 1.7 mmol) was added, and the mixture wasstirred for 15 minutes. The solvent was evaporated, and the residue waspurified by flash column chromatography (Silica gel, methanol/methylenechloride 4%/96%) to give2-(4-chloro-phenyl)-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-acetamideas a white solid (550 mg, 70% yield); HPLC, Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, grad. to 95/5 in 5min, kept 5 min, 6.00 min (98.7%); mp, 229.5-231.5° C.; ¹HNMR (DMSO-d₆)δ 2.15-2.21 (m, 1H, CHH), 2.57-2.89 (m, 6H, CHCH₂, CH), 3.50 (s, 2H,ArCH₂), 4.37 (d, J=5 Hz, 2H, CH₂NH), 5.26 (dd, J=6, 11 Hz, 1H, CH),7.27-7.90 (m, 7H, Ar), 8.67 (t, J=5 Hz, 1H, CH₂NH), 11.03 (s, 1H, NH);¹H NMR (DMSO-d₆) δ 20.92, 23.40, 30.63, 41.39, 41.87, 56.53, 120.02,123.99, 126.57, 128.13, 130.87, 131.09, 134.03, 135.21, 137.97, 145.81,154.61, 160.38, 169.47, 169.85, 172.61. LCMS MH=453, 455; Anal Calcd ForC₂₃H₂₁N₄O₄Cl: C, 61.00; H, 4.67; N, 12.37; Cl, 7.83. Found: C, 60.88; H,4.60; N, 12.27; Cl, 7.89.

5.17 1-[3-(2,6-DIOXO-PIPERIDIN-3-Y L)-2-METHYL-1-OXO-3,4-DIHYDRO-QUINAZOLIN-6-YLMETHYL]-3-HEXYL-UREA

To a stirred suspension of3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.50 g, 1.5 mmol) and triethylamine (0.29 mL, 2.1mmol) in THF (12 mL) at 5-10° C., was added hexyl isocyanate (0.25 g,1.9 mmol), and the mixture was stirred at room temperature overnight.The mixture was quenched with methanol (−1 mL), and the solvent wasevaporated. The residue was purified by flash column chromatography(Silica gel, methanol/methylene chloride 4%/96%) to give1-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-hexyl-ureaas an off-white solid (410 mg, 65% yield); HPLC, Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, grad. to 95/5in 5 min, kept 5 min, 6.05 min (99.0%); mp, 220-222° C.; ¹HNMR (DMSO-d₆)δ 0.85 (t, J=6 Hz, 3H, CH₃CH₂CH₂), 1.24-1.38 (m, 8H, CH₂CH₂CH₂CH₂),2.15-2.20 (m, 1H, CHH), 2.56-3.03 (m, 6H, CHCH₂, CHO, 4.30 (d, J=6 Hz,2H, ArCH₂NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 5.97 (t, J=5 Hz, 1H,CH₂NH), 6.40 (t, J=6 Hz, 1H, ArCH₂NH), 7.55-7.89 (m, 3H, Ar), 11.02 (s,1H, NH); ¹³C NMR (DMSO-d₆) δ 13.88, 20.93, 22.05, 23.38, 26.03, 29.94,30.63, 31.02, 39.35, 42.44, 56.51, 119.96, 123.46, 126.40, 133.81,139.87, 145.64, 154.36, 157.99, 160.46, 169.47, 172.60. LCMS MH=428;Anal Calcd For C₂₂H₂₉N₅O₄: C, 61.81; H, 6.84: N, 16.38. Found: C, 61.50;H, 6.82; N, 16.23.

5.181-(4-CHLORO-PHENYL)-3-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-6-YLMETHYL]-UREA

To a stirred suspension of3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.47 g, 1.4 mmol) and triethylamine (0.27 mL, 2.0mmol) in THF (8 mL) at 5˜10° C., was added 4-chlorophenyl isocyanate(0.28 g, 1.8 mmol), and the mixture was stirred at room temperatureovernight. The mixture was quenched with methanol (−1 mL), and thesolvent was evaporated. The residue was purified by flash columnchromatography (Silica gel, methanol/methylene chloride 4%/96%) to give1-(4-chloro-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-ureaas an off-white solid (400 mg, 63% yield); HPLC, Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, grad. to 95/5in 5 min. kept 5 min, 6.18 min (98.9%); mp, 225-227° C.; ¹HNMR (DMSO-d₆)δ 2.15-2.20 (m, 1H, CHH), 2.56-2.91 (m, 6H, CHCH₂, CH), 4.41 (d, J=5 Hz,2H, CH₂NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 6.81 (t, J=6 Hz, 1H, CH₂NH),7.23-7.95 (m, 7H, Ar), 8.80 (s, 1H, NH), 11.02 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 20.93, 23.38, 30.61, 42.33, 56.54, 119.23, 120.01, 123.67,124.57, 126.53, 128.42, 133.95, 139.05, 139.37, 145.74, 154.53, 155.09,160.46, 169.47, 172.60. LCMS MH=454, 456; Anal Calcd ForC₂₂H₂₀N₅O₄Cl+0.8H₂O: C, 56.43; H, 4.65; N, 14.95; Cl, 7.57. Found: C,56.45; H, 4.56; N, 14.87; Cl, 7.69.

5.19 1-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-6-YLMETHYL]-3-M-TOLYL-UREA

To a stirred suspension of3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.50 g, 1.5 mmol) and triethylamine (0.29 mL, 2.1mmol) in THF (12 mL) at 5˜10° C., was added m-toluoyl isocyanate (0.25mL, 1.9 mmol), and the mixture was stirred at room temperatureovernight. The mixture was quenched with methanol (˜1 mL), and thesolvent was evaporated. The residue was purified by flash columnchromatography (Silica gel, methanol/methylene chloride 4%/96%) to give1-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-m-tolyl-ureaas an off-white solid (437 mg, 68% yield); HPLC, Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, grad. to 95/5in 5 min, kept 5 min, 5.95 min (99.0%); mp, 200-202° C.; ¹HNMR (DMSO-d₆)δ 2.07-2.24 (m, 4H, ArCH₃, CHH), 2.56-2.88 (m, 6H, CHCH₂, CH₃), 4.40 (d,J=5 Hz, 2H, CH₂NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 6.70-7.95 (m, 8H, Arand CH₂NH), 8.54 (s, 1H, NH), 11.01 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ20.92, 21.19, 23.39, 30.61, 42.30, 56.53, 114.93, 118.27, 120.00,121.87, 123.63, 126.53, 128.44, 133.94, 137.70, 139.23, 140.26, 145.73,154.50, 155.22, 160.46, 169.48, 172.61. LCMS MH=434; Anal Calcd ForC₂₃H₂₃N₅O₄+1.4H₂O: C, 60.23; H, 5.67; N, 15.27. Found: C, 60.18; H,5.44; N, 15.09.

5.201-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-6-YLMETHYL]-3-(4-TRIFLUOROMETHOXY-PHENYL)-UREA

To a stirred suspension of3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.49 g, 1.5 mmol) and triethylamine (0.28 mL, 2.1mmol) in THF (12 mL) at 5-10° C., was added trifluoromethoxy-phenylisocyanate (0.29 mL, 1.9 mmol), and the mixture was stirred at roomtemperature overnight. The mixture was quenched with methanol (−1 mL),and the solvent was evaporated. The residue was purified by flash columnchromatography (Silica gel, methanol/methylene chloride 4%/96%) to give1-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-(4-trifluoromethoxy-phenyl)-ureaas an off-white solid (490 mg, 67% yield); HPLC, Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CF₃CN/0.1% F₃PO₄, grad. to 95/5in 5 min, kept 5 min, 6.47 min (98.6%); mp, 201-203° C.; ¹HNMR (DMSO-d₆)δ 2.15-2.20 (m, 1H, CHH), 2.56-2.90 (m, 6H, CHCH₂, CH₃), 4.42 (d, J=5Hz, 211, CH₂NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 6.84 (t, J=6 Hz, 1H,CH₂NH), 7.21-7.96 (m, 7H, Ar), 8.88 (s, 1H, NH), 11.02 (s, 1H, NH); ¹³CNMR (DMSO-d₆) δ 20.93, 23.39, 30.61, 42.33, 56.53, 118.81, 120.01,120.17 (q, J_(C-F)=255 Hz), 121.54, 123.66, 126.54, 133.93, 139.04,139.69, 142.08, 145.76, 154.52, 155.12, 160.46, 169.48, 172.60. LCMSMH=504; Anal Calcd For C₂₁H₂₀N₅O₅F₃+0.2H₂O: C, 54.48; H, 4.06; N, 13.81;F, 11.24. Found: C, 54.25; H, 4.00; N, 13.59; F, 11.24.

5.21N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-6-YLMETHYL]-4-TRIFLUOROMETHYLSULFANYL-BENZAMIDE

To a stirred suspension of3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.47 g, 1.4 mmol) in acetonitrile (10 mL), was added4-trifluoromethylthio-benzoyl chloride (0.35 mL, 2.1 mmol) andN,N-diisopropyl ethylamine (0.58 mL, 3.5 mmol). The mixture was stirredat room temperature for one hour. The solvent was evaporated, and theresidue was purified by flash column chromatography (Silica gel,methanol/methylene chloride 4%/96%) to giveN-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-4-trifluoromethyl-sulfanyl-benzamideas an off-white solid (470 mg, 66% yield); HPLC, Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, gradient to95/5 in 5 min, kept for 5 min, 6.63 min (96.8%); mp, 169-171° C.; ¹HNMR(DMSO-d₆) δ 2.15-2.20 (m, 1H, CHH), 2.56-2.86 (m, 6H, CHCH₂, CH₃), 4.60(d, J=5 Hz, 2H, CH₂NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.59-8.03 (m, 7H,Ar), 9.35 (t, J=5 Hz, 1H, CH₂NH), 11.02 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ20.89, 23.41, 30.60, 42.38, 56.52, 120.01, 123.90, 126.33, 126.64,128.64, 129.46 (q, J_(C-F)=307 Hz), 134.09, 135.91, 136.69, 137.86,145.85, 154.64, 160.41, 165.28, 169.47, 172.62. LCMS MH=505; Anal CalcdFor C₂₃H₁₉N₄O₄F₃S+0.8H₂O: C, 53.24; H, 4.00; N, 10.80; F, 10.98; S,6.18. Found: C, 53.17; H, 3.83; N, 10.60; F, 10.74; S, 6.14.

5.221-(3-CHLORO-4-METHYL-PHENYL)-3-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-6-YLMETHYL]-UREA

To a stirred suspension of3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.46 g, 1.4 mmol) and triethylamine (0.27 mL, 1.9mmol) in THF (10 mL) at 5-10° C., was added 3-chloro-4-methyl-phenylisocyanate (0.24 mL, 1.8 mmol), and the mixture was stirred at roomtemperature overnight. The mixture was quenched with methanol (˜1 mL),and the solvent was evaporated. The residue was purified by flash columnchromatography (Silica gel, methanol/methylene chloride 4%/96%) to give1-(3-chloro-4-methyl-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-ureaas an off-white solid (450 mg, 70% yield); HPLC, Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, grad. to 95/5in 5 min, kept 5 min, 6.38 min (98.4%); mp, 186-188° C.; ¹HNMR (DMSO-d₆)δ 2.15-2.23 (m, 4H, CHH and CH₃Ar), 2.56-2.86 (m, 6H, CHCH₂, CH₃), 4.40(d, J=6 Hz, 2H, CH₂NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 6.81 (t, J=5 Hz,1H, CH₂NH), 7.11-7.95 (m, 6H, Ar), 8.75 (s, 1H, NH), 11.02 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 18.71, 20.93, 23.39, 30.61, 42.34, 56.53, 116.45,117.66, 120.01, 123.67, 126.54, 127.39, 130.99, 132.96, 133.95, 139.05,139.58, 145.76, 154.51, 155.08, 160.47, 169.47, 172.60. LCMS MH=468,470; Anal Calcd For C₂₃H₂₂N₅O₄Cl+0.6H₂O: C, 57.71; H, 4.88; N, 14.63;Cl, 7.41. Found: C, 57.63; H, 4.96; N, 14.50; Cl, 7.64.

5.234-CHLORO-N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-6-YLMETHYL]-BENZAMIDE

To a stirred suspension of3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.54 g, 1.6 mmol) in acetonitrile (10 mL), was added4-dichloro-benzoyl chloride (0.31 mL, 2.4 mmol) and N,N-diisopropylethylamine (0.66 mL, 4.0 mmol). The mixture was stirred at roomtemperature for 30 minutes. The solvent was evaporated, and the residuewas purified by flash column chromatography (Silica gel,methanol/methylene chloride 4%/96%) to give4-chloro-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-benzamideas a white solid (298 mg, 42% yield); HPLC, Waters Symmetry C_(u), 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, gradient to 95/5in 5 min, kept for 5 min, 6.00 min (99.0%); mp, 267-269° C.; ¹HNMR(DMSO-d₆) δ 2.15-2.18 (m, 1H, CHH), 2.57-2.85 (m, 6H, CHCH₂, CH₃), 4.59(d, J=5 Hz, 2H, CH₂NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.54-7.95 (m, 7H,Ar), 9.24 (t, J=5 Hz, 1H, CH₂NH), 11.02 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ20.91, 23.40, 30.60, 42.33, 56.52, 120.01, 123.89, 126.62, 128.44,129.15, 132.84, 134.09, 136.16, 138.02, 145.83, 154.60, 160.43, 165.23,169.45, 172.60. LCMS MH=439, 441; Anal Calcd For C₂₂H₁₉N₄O₄Cl+0.3H₂O: C,59.48; H, 4.45; N, 12.61; Cl, 7.98. Found: C, 59.32; H, 4.10; N, 12.50;Cl, 7.99.

5.24N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-6-YLMETHYL]-3-TRIFLUOROMETHYL-BENZAMIDE

To a stirred solution of 3-trifluoromethyl-benzoic acid (0.30 g, 1.6mmol) in DMF (8 mL) in a 40° C. oil bath, was added 1,1′carbonyldiimidazole (0.28 g, 1.7 mmol), and the mixture was stirred forone hour. Then3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.53 g, 1.6 mmol) was added, and the mixture wasstirred for 15 minutes. The solvent was evaporated, and the residue waspurified by flash column chromatography (Silica gel, methanol/methylenechloride 4%/96%) to giveN-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-trifluoromethyl-benzamideas an off-white solid (430 mg, 59% yield); HPLC, Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% F₃PO₄, grad. to 95/5in 5 min, kept 5 min. 6.20 min (98.5%); mp, 220-222° C.; ¹HNMR (DMSO-d₆)δ 2.15-2.20 (m, 1H, CHH), 2.56-2.91 (m, 6H, CHCH₂, CH₃), 4.62 (d, J=5Hz, 2H, CH₂NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.59-8.25 (m, 7H, Ar),9.42 (t, J=5 Hz, 1H, CH₂NH), 11.02 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ20.90, 23.41, 30.60, 42.45, 56.53, 120.02, 123.79 (q, J_(C-F)=11 Hz),123.79 (d, J_(C-F)=3 Hz), 123.95 (q, J_(C-F)=275 Hz), 124.04, 126.67,127.96 (d, J_(C-F)=3 Hz), 129.19 (d, J_(C-F)=32 Hz), 129.74, 131.38,134.18, 134.88, 137.81, 145.88, 154.65, 160.43, 164.73, 169.45, 172.59.LCMS MH=473; Anal Calcd For C₂₃H₁₉N₄O₄F₃+0.3H₂O: C, 57.81; H, 4.13; N,11.73; F, 11.93. Found: C, 57.77; H, 4.11; N, 11.69; F, 11.97.

5.25N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-6-YLMETHYL]-4-TRIFLUOROMETHOXY-BENZAMIDE

To a stirred suspension of3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.49 g, 1.4 mmol) in acetonitrile (10 mL), was added4-trifluoromethoxy-benzoyl chloride (0.34 mL, 2.2 mmol) andN,N-diisopropyl ethylamine (0.63 mL, 3.6 mmol). The mixture was stirredat room temperature for one hour. The solvent was evaporated, and theresidue was purified by flash column chromatography (Silica gel,methanol/methylene chloride 4%/96%) to giveN-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-4-trifluoromethoxy-benzamideas an off-white solid (500 mg, 71% yield); HPLC, Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, gradient to95/5 in 5 min, kept for 5 min, 6.40 min (99.5%); mp, 165-167° C.; ¹HNMR(DMSO-d₆) δ 2.15-2.20 (m, 1H, CHH), 2.56-2.88 (m, 6H, CHCH₂, CH₃), 4.60(d, J=5 Hz, 2H, CH₂NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.458-8.04 (m,7H, Ar), 9.28 (t, J=5 Hz, 1H, CH₂NH), 11.02 (s, 1H. NH); ¹³C NMR(DMSO-d₆) δ 20.90, 23.40, 30.60, 42.35, 56.53, 119.93 (q, J_(C-F)=257Hz), 120.01, 120.67, 123.87, 126.62, 129.56, 133.19, 134.17, 134.07,137.97, 145.83, 150.35, 154.61, 160.43, 165.06, 169.45, 172.59. LCMSMH=489; Anal Calcd For C₂₂H₁₉N₄O₅F₃+1.1H₂O: C, 54.36; H, 4.20; N, 11.02;F, 11.21. Found: C, 54.40; H, 3.89; N, 10.67; F, 11.06.

5.263,4-DICHLORO-N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-6-YLMETHYL]-BENZAMIDE

To a stirred suspension of3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.45 g, 1.4 mmol) in acetonitrile (10 mL), was added3,4-dichloro-benzoyl chloride (0.34 g, 1.6 mmol) and N,N-diisopropylethylamine (0.54 mL, 3.2 mmol). The mixture was stirred at roomtemperature for 15 minutes. The solvent was evaporated, and the residuewas purified by flash column chromatography (Silica gel,methanol/methylene chloride 4%/96%) to give3,4-dichloro-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-benzamideas an off-white solid (290 mg, 46% yield); HPLC, Waters Symmetry C₁₈, 5nm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% F₃PO₄, gradient to95/5 in 5 min, kept for 5 min, 6.45 min (99.6%); mp, 177-179° C.; ¹HNMR(DMSO-d₆) δ 2.16-2.18 (m, 1H, CHH), 2.56-2.84 (m, 6H, CHCH₂, CH), 4.59(d, J=5 Hz, 2H, CH₂NH), 5.26 (dd, J=5, 9 Hz, 1H, CH), 7.58-8.14 (m, 6H,Ar), 9.34 (t, J=5 Hz, 1H, CH₂NH), 11.02 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ20.91, 23.41, 30.61, 42.47, 56.54, 120.01, 124.04, 126.66, 127.56,129.20, 130.77, 131.32, 134.17, 134.37, 137.71, 145.88, 154.65, 160.42,164.00, 169.45, 172.60. LCMS MH=473, 475; Anal Calcd ForC₂₂H₁₈N₄O₄Cl₂+1.0 CH₂Cl₂: C, 53.78; H, 4.10; N, 11.40; Cl, 14.43. Found:C, 53.44; H, 4.11; N, 11.27; Cl, 14.80.

5.27N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-6-YLMETHYL]-4-TRIFLUOROMETHYL-BENZAMIDE

To a stirred solution of 4-trifluoromethyl-benzoic acid (0.30 g, 1.6mmol) in DMF (8 mL) in a 40° C. oil bath, was added 1.1°carbonyldiimidazole (0.29 g, 1.8 mmol), and the mixture was stirred forone hour. Then3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.54 g, 1.6 mmol) was added, and the mixture wasstirred for 15 minutes. The solvent was evaporated, and the residue waspurified by flash column chromatography (Silica gel, methanol/methylenechloride 4%/96%) to giveN-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-4-trifluoromethyl-benzamideas an off-white solid (500 mg, 67% yield); HPLC, Waters Symmetry C₁₈, 5nm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, grad. to 95/5in 5 min, kept 5 min, 6.33 min (99.1%); mp, 221-223° C.; ¹HNMR (DMSO-d₆)δ 2.14-2.20 (m, 1H, CHH), 2.56-2.88 (m, 6H, CHCH₂, CH₃), 4.62 (d, J=5Hz, 2H, CH₂NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.59-8.11 (m, 7H, Ar),9.40 (t, J=5 Hz, 1H, CH₂NH), 11.02 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ20.90, 23.41, 30.60, 42.41, 56.53, 120.03, 123.90 (q, J_(C-F)=253 Hz),123.95, 125.36 (d, J_(C-F)=3 Hz), 125.45 (d, J_(C-F)=3 Hz), 126.65,128.14, 131.23 (d, J_(C-F)=31 Hz), 134.11, 137.83, 145.87, 154.64,160.42, 165.12, 169.45, 172.59. LCMS MH=473; Anal Calcd ForC₂₃H₁₉N₄O₄F₃: C, 58.48; H, 4.05; N, 11.86; F, 12.06. Found: C, 58.36; H,3.96; N, 11.75; F, 11.84.

5.28 3-(2,7-DIMETHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

To a stirred mixture of 2-amino-4-methylbenzoic acid (2.0 g, 13 mmol)and imidazole (1.1 g, 16 mmol) in acetonitrile (20 mL), was added acetylchloride (1.1 mL, 16 mmol) at room temperature. The mixture was stirredat room temperature overnight. To the mixture, was added3-amino-piperidine-2,6-dione hydrogen chloride (2.2 g, 13 mmol),imidazole (2.0 g, 30 mmol) and triphenyl phosphite (4.2 mL, 16 mmol) andheated to reflux for 22 hours. To the mixture, was added water (60 mL).The suspension was filtered and washed with water (2×50 mL), ethylacetate (2×50 mL), and water (50 mL) to give3-(2,7-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as awhite solid (2.52 g, 67% yield): HPLC: Waters Symmetry C₁₃, 5 μM,3.9×150 mm, 1 mL/min. 240 nm, 20/80 CH₃CN/0.1% H₃PO₄, 5.13 min (99.9%);mp: 305° C. (decomp); ¹H NMR (DMSO-d₆) δ 2.08-2.24 (m, 1H, CHH), 2.45(s, 3H, CH₃), 2.56-2.75 (m, 5H, 2CHH), 2.81-2.91 (m, 1H, CHH), 5.24 (dd,J=6, 11 Hz, 1H, NCH), 7.32 (dd, J=1.8 Hz 1H, Ar), 7.43 (s, 1H, Ar), 7.91(d, J=8 Hz, 1H, Ar), 11.00 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 21.00,21.35, 23.45, 30.61, 56.43, 117.94, 125.80, 126.10, 127.97, 145.21,146.98, 154.96, 160.34, 169.56, 172.62; LCMS: MH=286; Anal Calcd forC₁₅H₁₅N₃O₃: C, 63.15; H, 5.21; N, 14.73. Found: C, 63.14; H, 5.21; N,14.76.

5.29 3-(7-FLUORO-2-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

To a stirred mixture of 2-amino-4-fluorobenzoic acid (2.5 g, 16 mmol)and imidazole (1.3 g, 19 mmol) in acetonitrile (25 mL), was added acetylchloride (1.4 mL, 19 mmol) at room temperature. The mixture was stirredat room temperature overnight. To the mixture, was added3-amino-piperidine-2,6-dione hydrogen chloride (2.7 g, 16 mmol),imidazole (2.4 g, 36 mmol) and triphenyl phosphite (5.1 mL, 19 mmol) andheated to reflux for 22 hours. To the mixture, was added water (60 mL).The suspension was tittered and washed with water (2×50 mL), ethylacetate (2×50 mL), and water (50 mL) to give3-(7-fluoro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as awhite solid (2.5 g, 52% yield): HPLC: Waters Symmetry C₁₈, 5 μm, 3.9×150mm, 1 mL/min, 240 nm, 25/75 CH₃CN/0.1% H₃PO₄, 3.83 min (100%); mp:243-245° C.; ¹H NMR (DMSO-d₆) δ 2.15-2.22 (m, 1H, CHH), 2.58-2.71 (m,5H, CH₃, 2CHH), 2.79-2.86 (m, 1H, CHH), 5.28 (dd, J=5, 11 Hz, 1H, NCH),7.34-7.44 (m, 2H, Ar), 8.10 (dd, J=6, 9 Hz, 1H, Ar), 11.05 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 20.89, 23.50, 30.58, 56.59, 111.62 (d, J_(C-F)=22Hz), 115.26 (d, J_(C-F)=24 Hz), 117.32, 129.19 (d, J_(C-F)=11 Hz),148.97 (d, J_(C-F)=13 Hz), 156.65, 159.77, 165.83 (d, J_(C-F)=252 Hz),169.41, 172.59; LCMS: MH=290; Anal Calcd for C₁₄H₁₂N₃O₃F: C, 58.13; H,4.18; N, 14.53; F, 6.57. Found: C, 58.09; H, 4.08; N, 14.42; F, 6.72.

5.30 3-(7-CHLORO-2-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

To a stirred mixture of 2-amino-4-chlorobenzoic acid (5.0 g, 29 mmol)and imidazole (2.4 g, 35 mmol) in acetonitrile (50 mL), was added acetylchloride (2.5 mL, 35 mmol) at room temperature. The mixture was stirredat room temperature overnight. To the mixture, was added3-amino-piperidine-2,6-dione hydrogen chloride (4.8 g, 29 mmol),imidazole (4.4 g, 64 mmol) and triphenyl phosphite (8.4 mL, 32 mmol) andheated to reflux for 22 hours. The suspension was filtered and washedwith acetonitrile (50 mL) and water (2×50 mL) to give3-(7-chloro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as awhite solid (6.5 g, 73% yield): HPLC: Waters Symmetry C₁₈, 5 μm, 3.9×150mm, 1 mL/min, 240 nm, 30/70 CH₃CN/0.1% H₃PO₄, 4.36 min (99.9%); mp:291-293° C.; ¹H NMR (DMSO-d₆) δ 2.16-2.23 (m, 1H, CHH), 2.59-2.72 (m,5H, CH₃, 2CHH), 2.79-2.92 (m, 1H, CHH), 5.29 (dd, J=5, 11 Hz, 1H, NCH),7.53 (dd, J=2.9 Hz, 1H, Ar), 7.69 (d, J=8 Hz, 1H, Ar), 8.03 (d, J=8 Hz,1H. Ar), 11.07 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 20.84, 23.53, 30.58,56.65, 19.06, 125.70, 126.91, 128.07, 139.30, 147.89, 156.74, 159.89,169.35, 172.58; LCMS: MH=306, 308; Anal Calcd for C₁₄H₁₂N₃O₃Cl: C,55.00; H, 3.96; N, 13.74; Cl, 11.60. Found: C, 55.24; H, 3.78; N, 13.74;Cl, 12.01.

5.31 3-(7-BROMO-2-METHYL-4H-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

To a stirred mixture of 2-amino-4-bromobenzoic acid (2.0 g, 9.3 mmol)and imidazole (0.8 g, 11 mmol) in acetonitrile (20 mL), was added acetylchloride (0.8 mL, 11 mmol) at room temperature. The mixture was stirredat room temperature overnight. To the mixture, was added3-amino-piperidine-2,6-dione hydrogen chloride (1.5 g, 9.3 mmol),imidazole (1.4 g, 20 mmol) and triphenyl phosphite (2.9 mL, 11 mmol) andheated to reflux for 22 hours. To the mixture, was added water (30 mL).The suspension was filtered and washed with water (2×50 mL), ethylacetate (2×50 mL), and water (50 mL) to give3-(7-bromo-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as awhite solid (2.4 g, 75% yield): HPLC: Waters Symmetry C₁₈, 5 μm, 3.9×150mm, 1 mL/min, 240 nm, 20/80 CH₃CN/0.1% H₃PO₄, 18.65 min (98.9%); mp:315-317° C.; ¹HNMR (DMSO-d₆) δ 2.08-2.22 (m, 1H, CHH), 2.62-2.79 (m, 5H,CH₃, 2CHH), 2.80-2.91 (m, 1H, CHH), 5.28 (dd, J=6, 11 Hz, 1H, NCH), 7.66(dd, J=2, 8 Hz, 1H, Ar), 7.84 (d, J=2 Hz 2H, Ar), 7.95 (d, J=8 Hz, 1H,Ar), 11.05 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 20.83, 23.53, 24.02, 30.58,56.67, 119.36, 128.06, 128.29, 128.80, 129.67, 147.93, 156.69, 160.02,169.33, 172.57; LCMS: MH=350, 352; Anal Calcd for C₁₄H₁₂N₃O₃Br: C,48.02; H, 3.45; N, 12.00; Br, 22.82. Found: C, 47.94; H, 3.17; N, 11.85;Br, 20.65.

5.323-(2-METHYL-4-OXO-7-TRIFLUOROMETHYL-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

To a stirred mixture of 2-amino-4-(trifluoromethyl)benzoic acid (3.0 g,15 mmol) and imidazole (1.2 g, 18 mmol) in acetonitrile (30 mL), wasadded acetyl chloride (1.3 mL, 18 mmol) at room temperature. The mixturewas stirred at room temperature overnight. To the mixture, was added3-amino-piperidine-2,6-dione hydrogen chloride (2.4 g, 15 mmol),imidazole (2.2 g, 32 mmol) and triphenyl phosphite (4.6 mL, 18 mmol) andheated to reflux for 22 hours. To the mixture, was added water (100 mL).The suspension was filtered and washed with water (2×50 mL), ethylacetate (2×50 mL), sodium hydrogen carbonate (sat, 50 mL) and water (50mL) to give a white solid, which was dissolved in DMSO (10 mL). To thesolution, was added water (3 mL) to give a suspension. The suspensionwas filtered and washed with DMSO (2 mL) to give a white solid. Thesolid was stirred in water (50 mL) at 60° C. for 2 hours, then at roomtemperature overnight. The suspension was filtered and washed with water(2×50 mL) to give3-(2-methyl-4-oxo-7-trifluoromethyl-4H-quinazolin-3-yl)-piperidine-2,6-dioneas a white solid (1.17 g, 24% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH₃CN/0.1% F₃PO₄, 8.14 min (99.9%);mp: 277-279° C.; ¹H NMR (DMSO-d₆) δ 2.18-2.25 (m, 1H, CHH), 2.59-2.74(m, 5H, CH₃, 2CHH), 2.81-2.88 (m, 1H, CHH), 5.34 (dd, J=6, 11 Hz, 1H,NCH), 7.80 (dd, J=2, 8 Hz, 1H, Ar), 7.96 (s, 1H. Ar), 8.24 (d, J=8 Hz,1H, Ar), 11.09 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 20.73, 23.54, 30.57,56.82, 122.30 (q, J_(C-F)=3 Hz), 122.99, 123.45 (q, J_(C-F)=273 Hz),123.74 (q, J_(C-F)=4 Hz), 127.85, 134.22 (q, J_(C-F)=32 Hz), 146.84,156.98, 159.80, 169.24, 172.56; LCMS: MH=340; Anal Calcd forC₁₅H₁₂N₃O₃F₁: C, 53.10; H, 3.57; N, 12.39; F, 16.80. Found: C, 52.55; H,3.42; N, 12.21; F, 17.18.

5.33 3-(7-FLUORO-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

Step 1: A mixture of 2-amino-4-fluorobenzoic acid (2.5 g, 16 mmol) andCDI (2.4 g, 15 mmol) in acetonitrile (30 mL) was stirred at roomtemperature for 1.5 hours. To the suspension, was added3-amino-piperidine-2,6-dione hydrogen chloride (2.4 g, 15 mmol) andsodium hydrogen carbonate (1.6 g, 19 mmol), and the mixture was heatedat 50° C. for 21 hours. The suspension was cooled to room temperaturefor 1 hour. The suspension was filtered and washed with acetonitrile (5mL) and water (2×20 mL). The solid was stirred in methanol (15 mL)overnight. The suspension was filtered and washed with methanol (15 mL)to give 2-amino-N-(2,6-dioxo-piperidin-3-yl)-4-fluorobenzamide as anoff-white solid (1.9 g, 45% yield): ¹H NMR (DMSO-d₆) δ 1.91-1.96 (m, 1H,CHH), 2.04-2.18 (m, 1H, CHH), 2.50-2.56 (m, 1H, CHH), 2.73-2.85 (m, 1H,CHH), 4.67-4.76 (m, 1H, NCH), 6.35 (dt, J=2, 9 Hz, 1H, Ar), 6.48 (dd,J=2, 12 Hz, 1H, Ar), 6.76 (brs, 2H. NH₂), 7.58 (dd; J=7, 8 Hz, 1H, Ar),8.50 (d, J=8 Hz, 1H, NH), 10.84 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 24.06,30.91, 48.98, 101.30 (d, J_(C-F)=23 Hz), 101.60 (d, J_(C-F)=22 Hz),110.60, 130.66 (d, J_(C-F)=11 Hz), 152.16 (d, J_(C-F)=12 Hz), 164.46 (d.J_(C-F)=246 Hz), 167.80, 172.30, 172.94.

Step 2: A solution of2-amino-N-(2,6-dioxo-piperidin-3-yl)-4-fluoro-benzamide (0.9 g, 3.4mmol) and trimethyl orthoformate (4 mL) and p-toluene sulfonic acid (110mg) was heated to 160° C. in a microwave oven for 15 minutes. To themixture, was added methanol (10 mL), and the mixture was stirred for 10minutes. The suspension was filtered and washed with methanol to give3-(7-fluoro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a whitesolid (650 mg, 70% yield): HPLC: Waters Symmetry C₁₈, 5 μm, 3.9×150 mm,1 mL/min, 240 nm, 30/70 CH₃CN/0.1% H₃PO₄, 2.45 min (96.1%); mp: 296-298°C.; ¹H NMR (DMSO-d₆) δ 2.13-2.19 (m, 1H, CHH), 2.63-2.73 (m, 2H, 2CHH),2.82-2.93 (m, 1H, CHH), 5.50 (br, 1H, NCH), 7.46 (dt, J=3, 9 Hz, 1H,Ar), 7.53 (dd, J=3.10 Hz, 1H, Ar), 8.22 (dd, J=6, 9 Hz, 1H, Ar), 8.42(s, 1H, CH), 11.18 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.45, 30.88, 56.43,112.3 (d, J_(C-F)=22 Hz), 115.91 (d, J_(C-F)=23 Hz), 118.38, 129.32 (d,J_(C-F)=11 Hz), 148.71, 149.65 (d. J_(C-F)=14 Hz), 159.00, 165.70 (d,J_(C-F)=252 Hz), 169.76, 172.41; LCMS: MH=276; Anal Calcd forC₁₃H₁₀N₃O₃F: C, 56.73; H, 3.66; N, 15.27. Found: C, 56.39; H, 3.60; N,15.16.

5.34 3-(7-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

Step 1: A mixture of 2-amino-4-methylbenzoic acid (2.0 g, 13 mmol) andCDI (2.0 g, 12 mmol) in acetonitrile (20 mL) was stirred at roomtemperature for 1.5 hours. To the suspension, was added3-amino-piperidine-2,6-dione hydrogen chloride (2.0 g, 12 mmol) andsodium hydrogen carbonate (1.3 g, 16 mmol), and the mixture was heatedat 50° C. for 21 hours. The suspension was cooled to room temperaturefor 1 hour. The suspension was filtered and washed with water (50 mL)and ethyl acetate (20 mL). The solid was dried in a vacuum ovenovernight to give2-amino-N-(2,6-dioxo-piperidin-3-yl)-4-methyl-benzamide as a white solid(2.2 g, 69% yield): ¹H NMR (DMSO-d₆) δ 1.90-1.96 (m, 1H, CHH), 2.05-2.14(m, 1H, CHH), 2.18 (s, 3H, CH₃), 2.49-2.55 (m, 1H, CHH), 2.72-2.84 (m,1H, CHH), 4.67-4.75 (m, 1H, NCH), 6.36 (dd, J=2, 8 Hz, 1H, Ar), 6.43(br, 2H, NHH, Ar), 6.51 (s, 1H, NHH), 7.43 (d, J=8 Hz, 1H, Ar), 8.38 (d,J=8 Hz, 1H, NH), 10.83 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 21.05, 24.21,30.99, 48.97, 111.26, 115.74, 116.48, 128.09, 141.71, 149.96, 168.54,172.50, 173.04; LCMS: MH=262.

Step 2: A solution of2-amino-N-(2,6-dioxo-piperidin-3-yl)-4-methyl-benzamide (1.0 g, 3.8mmol) and trimethyl orthoformate (10 mL) and p-toluene sulfonic acid(250 mg) was heated to 160° C. in a microwave oven for 30 minutes. Thesuspension was filtered and washed with methanol (20 mL), water (20 mL)and methanol (20 mL) to give3-(7-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as anoff-white solid (880 mg, 85% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 20/80 CF₃CN/0.1% H₃PO₄, 5.14 min (97.1%);mp: 313-315° C.; ¹H NMR (DMSO-d₆) δ 2.11-2.18 (m, 1H, CHH), 2.48 (s, 3H,CH), 2.61-2.74 (m, 2H, 2CHH), 2.82-2.92 (m, 1H, CHH), 5.46 (br, 1H.NCH), 7.41 (dd, J=1, 8 Hz, 1H, Ar), 7.53 (s, 1H, Ar), 8.03 (d, J=8 Hz,1H, Ar), 8.33 (s, 1H, CH), 11.15 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 21.23,22.51, 30.91, 56.74, 118.95, 125.93, 126.74, 128.66, 145.27, 147.35,147.59, 159.54, 169.88, 172.44; LCMS: MH=272; Anal Calcd forC₁₄H₁₃N₃O₃+0.1H₂O: C, 61.58; H, 4.87; N, 15.39. Found: C, 61.41; H,4.87; N, 15.15.

5.35 3-(7-AMINO-2-METHYL-4-OXO-4H-QUINAZOLIN-3-Y L)-PIPERIDINE-2,6-DIONE

Step 1: To a stirred mixture of 2-amino-4-nitrobenzoic acid (5.0 g, 28mmol) and imidazole (2.2 g, 33 mmol) in acetonitrile (50 mL), was addedacetyl chloride (2.3 mL, 33 mmol) at room temperature. The mixture wasstirred at room temperature overnight. To the mixture, was added3-amino-piperidine-2,6-dione hydrogen chloride (4.5 g, 28 mmol),imidazole (4.1 g, 60 mmol) and triphenyl phosphite (8.7 mL, 33 mmol),and heated to reflux for 22 hours. To the mixture, was added water (60mL). The suspension was filtered and washed with water (2×50 mL), ethylacetate (2×50 mL), and water (50 mL) to give3-(2-methyl-7-nitro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as anoff-white solid (4.8 g, 55% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, 5.69 min (95.4%);¹H NMR (DMSO-d₆) δ 2.15-2.25 (m, 1H, CHH), 2.59-2.69 (m, 2H, 2CHH), 2.70(s, 3H, CH₃), 2.79-2.87 (m, 1H, CHH), 5.35 (dd, J=6, 12 Hz, 1H, NCH),8.20-8.29 (m, 2H, Ar), 8.34 (d, J=2 Hz, 1H, Ar), 11.10 (s, 1H, NH); ¹³CNMR (DMSO-d₆) δ 20.60, 23.53, 30.49, 56.85, 120.26, 121.58, 124.35,128.30, 147.08, 151.30, 157.61, 159.52, 160.09, 172.48; LCMS: MH=317.

Step 2: A suspension of3-(2-methyl-7-nitro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (4.8g, 13 mmol) and 20% Pd(OH)₂/C (1.0 g) in cyclohexene (15 mL) and DMF (60mL) was heated in a 125° C. oil bath overnight. The suspension wasfiltered thru a pad of Celite, and washed with DMF (30 mL). To thefiltrate, was added water (150 mL) to give a suspension. The suspensionwas filtered and washed with water (50 mL) to give3-(7-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as anoff-white solid (3.07 g, 71% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 5/95 grad 95/5 in 5 min CH₃CN/0.1% H₃PO₄,4.08 min (97.3%) [sample was dissolved in 0.1% H₃PO₄]; mp: 305-307° C.;¹H NMR (DMSO-d₆) δ 2.05-2.16 (m, 1H, CHH), 2.53 (s, 3H, CH₃), 2.58-2.69(m, 2H, 2CHH), 2.75-2.86 (m, 1H, CHH), 5.10 (dd, J=6, 11 Hz, 1H, NCH),6.11 (brs, 2H, NH₂), 6.54 (d, J=2 Hz, 1H, Ar), 6.68 (dd, J=2, 8 Hz, 1H,Ar), 10.93 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 21.36, 23.43, 30.63, 55.97,106.12, 109.17, 114.70, 127.28, 148.95, 154.42, 154.61, 159.85, 169.87,172.67; LCMS: MH=287; Anal Calcd for C₁₄H₁₄N₄O₃: C, 58.74; H, 4.93; N,19.57. Found: C, 58.60; H, 4.83; N, 19.40.

5.36[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-7-YLMETHYL]-CARBAMICACID TERT-BUTYL ESTER

Step 1: To a stirred solution of 4-methyl-2-nitro-benzoic acid methylester (108.5 g, 555.7 mmol) in acetonitrile (750 mL), was added NBS(97.9 g, 550.1 mmol). The mixture was heated to a gentle reflex with a200 W light bulb on for 5.5 hours. The solvent was evaporated, and theresidue was dissolved in ethyl acetate (1500 mL). The solution waswashed with water (2×600 mL) and brine (300 mL), dried over magnesiumsulfate, and concentrated to give a brown oil. To the oil, was addedt-butyl methyl ether (300 mL). The mixture was heated at 70° C. for 15minutes. The mixture was allowed to cool to about 53° C. over one hour,then to 45° C., and then at 20-25° C., while blowing nitrogen with aglass pipette overnight. The suspension was filtered via a mediumpore-sized funnel. The solid was washed with a pre-cooled 10° C. mixedsolvent of heptane/MTBE (1/2 vol/vol) and suction dried in hoodovernight to give 4-bromomethyl-2-nitro-benzoic acid methyl ester as anoff-white solid (66 g, 43% yield). The solid was used in the next stepwithout further purification.

Step 2: A stirred mixture of 4-bromomethyl-2-nitro-benzoic acid methylester (66.3 g, 241.9 mmol), di-tert-butyl iminodicarboxylate (52.72 g,242.6 mmol), cesium carbonate (161.58 g, 495.9 mmol), and lithium iodide(1.62 g, 12 mmol) in 2-butanone (700 mL) was heated to reflux in a 100°C. oil bath for 12 hours while stirred with a mechanical stirrer. Themixture was allowed to cool to room temperature. To the mixture, wasadded brine (300 mL), water (300 mL), and ethyl acetate (600 mL), andthe mixture was stirred for 10 minutes. The suspension was filteredthrough a pad of Celite. The two layers were separated, and the organiclayer was evaporated to a less volume. The aqueous layer was extractedwith ethyl acetate (2×150 mL). The combined organic layers were washedwith brine (1×500 mL), dried over magnesium sulfate while de-colored atthe same time by charcoal at room temperature with stirring for 30minutes. The black mixture was filtered through a pad of Celite, and thefiltrate was evaporated to give4-(di-tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid methyl esteras a brown oil (96.0 g, 96.7% yield). The product was used in the nextstep without further purification.

Step 3: To a stirred brown solution of4-(di-tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid methyl ester(95.97 g, 233.8 mmol) in methylene chloride (800 mL), was addedtrifluoroacetic acid (33.87 mL, 455.9 mmol), and the mixture was stirredat room temperature overnight. Sat. sodium bicarbonate (500 mL) wasadded to the solution, and the mixture was stirred for 10 minutes. Theorganic layer was separated, dried over magnesium sulfate, andevaporated to give 4-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoicacid methyl ester as a brown oil (64.36 g, 88% crude yield). The productwas used in the next step without further purification.

Step 4: A mixture of 4-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoicacid methyl ester (64.36 g, 207.4 mmol), lithium hydroxide (5.96 g,248.9 mmol) in methanol (500 mL) and water (250 mL) was stirred with amechanical stirrer at room temperature overnight. The methanol wasevaporated, and to the aqueous solution, was added 1 N HCl (300 mL) toform the precipitate. Ether (350 mL) was added, and the mixture wasstirred at 0° C. for 2 hours. No desired precipitation was formed. Themixture was evaporated. To the mixture, was added water (500 mL). Theaqueous layer was extracted with ethyl acetate (5×120 mL). The combinedorganic layers were separated, dried over magnesium sulfate, andconcentrated to give 4-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoicacid as a brown oil (56.69 g, 92% yield). The product was used in thenext step without further purification.

Step 5: A mixture of 4-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoicacid (56.57, 190.9 mmol) in methanol (250 mL) and palladium/carbon (5.66g, 10% weight) was hydrogenated with a Parr-shaker overnight at 51 psi.The black mixture was filtered through a pad of Celite, and the filtratewas evaporated to give a brown oil, which was stirred in ether (300 mL)overnight. The ether slurry was filtered to give2-amino-4-(tert-butoxycarbonylamino-methyl)-benzoic acid as a brownsolid (42.0 g, 84% yield). The product was used in the next step withoutfurther purification.

Step 6: To a stirred solution of2-amino-4-(tert-butoxycarbonylamino-methyl)-benzoic acid (24.75 g, 92.94mmol), imidazole (7.59 g, 111.53 mmol) in acetonitrile (300 mL), wasadded acetyl chloride (7.96 mL, 111.53 mmol), and the mixture wasstirred at room temperature overnight. To the mixture, was added3-amino-piperidine-2,6-dione hydrogen chloride (15.30 g, 92.94 mmol),imidazole (12.66 g, 185.89 mmol) and triphenyl phosphite (29.23 mL,111.53 mmol), and the mixture was heated to reflux for 6 hours. Themixture was cooled to room temperature and the brown mixture wasfiltered. The filtrate was evaporated and then purified by flash columnchromatography (Silica gel, methanol/methylene chloride 4%/96%) to give[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-7-ylmethyl]-carbamicacid tert-butyl ester as a light yellow solid (24.57 g, 66% yield);HPLC, Waters Symmetry C₁₈, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90CF₃CN/0.1% H₃PO₄, grad. to 95/5 in 5 min, kept 5 min, 5.97 min (99.7%);mp, 240-242° C.; ¹HNMR (DMSO-d₆) δ 1.29 (brs, 1H, CH from the BOCgroup), 1.40 (s, 8H, 8CH from the BOC group), 2.11-2.19 (m, 1H, CHH),2.56-2.91 (m, 6H, CHCH₂, CH₃), 4.26 (d, J=6 Hz, 2H, CH₂NH), 5.25 (dd,J=5, 11 Hz, 1H, CH), 7.35-7.99 (m, 4H, Ar and NHCH₂), 11.02 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 20.97, 23.49, 28.19, 30.60, 43.22, 56.48, 78.00,118.84, 123.99, 125.41, 126.00, 146.93, 147.55, 155.15, 155.81, 160.29,169.51, 172.61. LCMS MH=401; Anal Calcd For C₂₀H₂₄N₄O₅: C, 59.99; H,6.04; N, 13.99. Found: C, 59.78; H, 5.78; N, 13.85.

5.373-(7-AMINOMETHYL-2-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONEHYDROGEN CHLORIDE

Step 1: To a stirred brown solution of[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-7-ylmethyl]-carbamicacid tert-butyl ester (14.7 g, 36.8 mmol) in methanol (200 mL) andmethylene chloride (200 mL), was added 2 M HCl in ether (320 mL), andthe mixture was stirred overnight. The solvent was evaporated, and theresidue was stirred in ether (100 mL) for 2 hours. The suspension wasfiltered to give3-(7-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride as a light yellow solid (13.2 g, 106% crude yield).The product was used in the next step without further purification.

Step 2:3-(7-Aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydro-chloride (1.00 g) was dissolved in water (100 mL). The solutionwas washed with ethyl acetate (2×100 mL). The aqueous layer wasevaporated to give3-(7-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride as an off-white solid (0.86 g, 86% yield); HPLC,Waters Xterra RP 18, Sum, 3.9×150 mm, 1 mL/min, 240 nm. Waters LC Module1, 05/95 CH₁CN/0.1% (HCO₂)NH₄, 6.27 min (98.7%); mp, 313-315° C.; ¹HNMR(DMSO-d₆) δ 2.17-2.24 (m, 1H, CHH), 2.58-2.89 (m, 6H, CHCH₂, CH₃), 4.20(q, J=5 Hz, 2H, ArCH₂), 5.34 (dd, J=6, 11 Hz, 1H, CH, hiding under thewater peak), 7.64-8.09 (m, 3H, Ar), 8.72 (brs, 3H, ClNH₃), 11.07 (s, 1H,NH); ¹³C NMR (DMSO-d₆) δ 20.88, 22.97, 30.57, 41.69, 56.71, 119.61,125.38, 126.42, 127.25, 141.34, 145.36, 156.66, 159.83, 169.25, 172.57.LCMS MH=301; Anal Calcd For C₁₅H₁₇N₄O₁Cl+1.0H₂O and +0.9HCl: C, 46.48;H, 5.17; N, 14.45; Cl, 17.38. Found: C, 46.68; H, 5.15; N, 14.32; Cl,17.05.

5.38 3-(2,8-DIMETHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

To a stirred mixture of 2-amino-3-ethylbenzoic acid (3.0 g, 20 mmol) andimidazole (1.6 g, 24 mmol) in acetonitrile (30 mL), was added acetylchloride (1.7 mL, 24 mmol) at room temperature. The mixture was stirredat room temperature overnight. To the mixture, was added3-amino-piperidine-2,6-dione hydrogen chloride (3.3 g, 20 mmol),imidazole (3.0 g, 68 mmol) and triphenyl phosphite (6.2 mL, 24 mmol) andheated to reflux for 22 hours. To the mixture, was added water (60 mL).The suspension was filtered and washed with water (2×100 mL), ethylacetate (2×100 mL), sodium hydrogen carbonate (sat, 100 mL) and water(100 mL) to give a white solid, which was stirred in DMSO (20 mL) at 65°C. The mixture was polished filtered and washed with DMSO (10 mL). Tothe filtrate, was added water (100 mL) to give a suspension. Thesuspension was filtered and washed with water (2×50 mL) to give3-(2,8-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as awhite solid (3.2 g, 56% yield): HPLC: Waters Symmetry C₁₈, 5 μm, 3.9×150mm, 1 mL/min, 240 nm, 25/75 CH₃CN/0.1% H₃PO₄, 5.85 min (99.6%); mp:296-298° C.; ¹H NMR (DMSO-d₆) δ 2.12-2.24 (m, 1H, CHH), 2.51 (s, 3H,CH₃), 2.48-2.74 (m, 2H, 2CHH), 2.66 (s, 3H, CH), 2.76-2.91 (m, 1H, CHH),5.27 (dd, J=6, 11 Hz, 1H, NCH), 7.38 (t, J=8 Hz, 1H, Ar), 7.67 (d, J=7Hz, 1H, Ar), 7.86 (dd, J=0.6, 8 Hz, 1H, Ar), 11.02 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 16.91, 20.91, 23.80, 30.60, 56.51, 120.23, 123.59, 126.05,134.72, 134.94, 145.25, 153.82, 160.71, 169.51, 172.62; LCMS: MH=286;Anal Calcd for C₁₅H₁₅N₃O₃+0.2H₂O: C, 62.36; H, 5.37; N, 14.54. Found: C,62.21; H, 5.31; N, 14.43.

5.39 3-(8-FLUORO-2-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

To a stirred mixture of 2-amino-3-fluorobenzoic acid (3.0 g, 19 mmol)and imidazole (1.6 g, 23 mmol) in acetonitrile (30 mL), was added acetylchloride (1.7 mL, 23 mmol) at room temperature. The mixture was stirredat room temperature overnight. To the mixture, was added3-amino-piperidine-2,6-dione hydrogen chloride (3.2 g, 19 mmol),imidazole (2.9 g, 43 mmol) and triphenyl phosphite (6.1 mL, 23 mmol) andheated to reflux for 22 hours. To the mixture, was added water (60 mL).The suspension was filtered and washed with water (2×50 mL), ethylacetate (2×50 mL), and water (50 mL) to give a white solid, which waspurified with preparative HPLC (C 18 20/80 CH3CN/H₂O) to give a whitesolid. The white solid in DMSO (20 mL) was heated at 60° C. for 30minutes. To the solution, was added water (10 mL). The suspension wascooled to room temperature. The suspension was filtered and washed withDMSO (4 mL) and water (20 mL) to give3-(8-fluoro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as awhite solid (3.11 g, 67% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 20/80 CH₃CN/0.1% H₃PO₄, 4.7 min (99.7%);mp: 305° C. (decomp); ¹H NMR (DMSO-d₆) δ 2.16-2.23 (m, 1H, CHH),2.43-2.76 (m, 5H, CH₃, 2CHH), 2.79-2.92 (m, 1H, CHH), 5.32 (dd, J=6, 11Hz, 1H, NCH), 7.46-7.53 (m, 1H. Ar), 7.67-7.73 (m, 1H, Ar), 7.84-7.94(m, 1H, Ar), 11.06 (s, 1H, NH); NMR (DMSO-d₆) δ 20.80, 23.67, 30.58,56.71, 120.04 (d, J_(C-F)=19 Hz), 121.71 (d, J_(C-F)=4 Hz), 122.31,126.91 (d, J_(C-F)=8 Hz), 136.04 (d, J_(C-F)=12 Hz), 155.93 (d,J_(C-F)=254 Hz), 155.93, 159.62 (d, J_(C-F)=3 Hz), 169.32, 172.57; LCMS:MH=290; Anal Calcd for C₁₄H₁₂N₃O₃F: C, 58.13; H, 4.18; N, 14.53; F,6.57. Found: C, 57.87; H, 3.94; N, 14.35; F, 6.91.

5.40 3-(8-CHLORO-2-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

To a stirred mixture of 2-amino-3-chlorobenzoic acid (2.2 g, 13 mmol)and imidazole (1.1 g, 16 mmol) in acetonitrile (30 mL), was added acetylchloride (1.1 mL, 16 mmol) at room temperature. The mixture was stirredat room temperature overnight. To the mixture, was added3-amino-piperidine-2,6-dione hydrogen chloride (2.3 g, 14 mmol),imidazole (1.9 g, 28 mmol) and triphenyl phosphite (4.0 mL, 15 mmol) andheated to reflux for 22 hours. To the mixture, was added water (60 mL).The suspension was filtered and washed with water (2×50 mL), ethylacetate (2×50 mL), and water (50 mL) to give a white solid, which wasstirred in methanol (50 mL) overnight. The suspension was filtered andwashed with methanol (30 mL) and water (30 mL) to give3-(8-chloro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as awhite solid (1.5 g, 38% yield): HPLC: Waters Symmetry C₁₈, 5 μm, 3.9×150mm, 1 mL/min, 240 nm, 25/75 CH₃CN/0.1% H₃PO₄, 6.51 min (99.6%); mp:290-292° C.; ¹H NMR (DMSO-d₆) δ 2.16-2.23 (m, 1H, CHH), 2.59-2.69 (m,5H, CH₃, 2CHH), 2.79-2.87 (m, 1H, CHH), 5.32 (dd, J=5, 11 Hz, 1H, NCH),7.48 (t, J=8 Hz, 1H. Ar), 7.96-8.02 (m, 2H, Ar), 11.07 (s, 1H, NH); ¹³CNMR (DMSO-d₆) δ 20.68, 23.75, 30.51, 56.68, 121.87, 125.08, 126.91,130.03, 134.69, 143.14, 156.14, 159.88, 169.23, 172.51; LCMS: MH=306,308; Anal Calcd for C₁₄H₁₂N₃O₃Cl: C, 55.00; H, 3.96; N, 13.74; Cl,11.60. Found: C, 54.73; H, 3.96; N, 13.58; Cl, 11.03.

5.41 3-(8-BROMO-2-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

To a stirred mixture of 2-amino-3-bromobenzoic acid (1.0 g, 4.6 mmol)and imidazole (0.38 g, 5.5 mmol) in acetonitrile (10 mL), was addedacetyl chloride (0.6 mL, 8.3 mmol) at room temperature. The mixture wasstirred at room temperature overnight. To the mixture, was added3-amino-piperidine-2,6-dione hydrogen chloride (0.76 g, 4.6 mmol),imidazole (0.7 g, 10 mmol) and triphenyl phosphite (1.5 mL, 5.6 mmol)and heated to reflux for 22 hours. To the mixture, was added water (60mL). The suspension was filtered and washed with water (2×50 mL), ethylacetate (2×50 mL), and water (50 mL) to give3-(8-bromo-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as awhite solid (0.34 g, 21% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 25/75 CH₃CN/0.1% H₃PO₄, 9.47 min (99.6%);mp: 307-309° C.; ¹H NMR (DMSO-d₆) δ 2.16-2.23 (m, 1H, CHH), 2.58-2.67(m, 2H, 2CHH), 2.68 (s, 3H, CH₃), 2.76-2.92 (m, 1H, CHH), 5.31 (dd, J=5,11 Hz, 1H. NCH), 7.41 (t, J=8 Hz, 1H, Ar), 8.04 (dd, J=2, 8 Hz 1H, Ar),8.15 (dd, J=1, 8 Hz 1H, Ar), 11.07 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ20.73, 23.85, 30.57, 56.76, 121.09, 121.82, 125.86, 127.47, 138.08,144.23, 156.23, 159.97, 169.29, 172.58; LCMS: MH=350, 352; Anal Calcdfor C₄H₁₂N₃O₃Br: C, 48.02; H, 3.45; N, 12.00; Br, 22.82. Found: C,47.74; H, 3.23; N, 11.85; Br, 22.42.

5.423-(8-HYDROXY-2-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

To a stirred mixture of 2-amino-3-hydroxybenzoic acid (2.0 g, 13.1 mmol)and imidazole (2.0 g, 29.4 mmol) in acetonitrile (30 mL), was addedacetyl chloride (2.0 mL, 28.7 mmol) at room temperature. The mixture wasstirred at room temperature overnight. To the mixture, was added3-amino-piperidine-2,6-dione hydrogen chloride (2.2 g, 13.1 mmol),imidazole (2.0 g, 29.4 mmol) and triphenyl phosphite (4.11 mL, 15.7mmol) and heated to reflux for 22 hours. To the mixture, was added water(60 mL) and cone HCl until pH 1. The solvent was removed in vacuo. Tothe residue, was added water (50 mL). The aqueous layer was extractedwith ethyl acetate (2×50 mL). To the aqueous layer, was added sodiumhydrogen carbonate (1.8 g) to pH=7-8, and the mixture was stirred atroom temperature to give a suspension. The suspension was filtered togive3-(8-hydroxy-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione asan off-white solid (0.6 g, 16% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 20/80 CF₃CN/0.1% H₃PO₄, 3.03 min (99.3%);mp: 266-268° C.; ¹H NMR (DMSO-d₆) δ 2.10-2.22 (m, 1H, CHH), 2.57-2.72(m, 5H, CH₃, 2CHH), 2.78-2.92 (m, 1H, CHH), 5.25 (dd, J=5, 11 Hz, 1H,NCH), 7.19 (dd, J=1, 8 Hz, 1H, Ar), 7.30 (t, J=8 Hz, 1H, Ar), 7.45 (dd,J=1, 8 Hz, 1H, Ar), 9.65 (s, 1H, OH), 11.02 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 20.92, 23.37, 30.59, 56.45, 115.62, 118.51, 121.19, 127.05,135.91, 152.34, 153.09, 160.45, 169.52, 172.62; LCMS: MH=288; Anal Calcdfor C₁₄H₁₃N₃O₄+1H₂O: C, 55.08; H, 4.95; N, 13.76. Found: C, 54.88; H,4.97; N, 13.77.

5.433-(2-METHYL-4-OXO-8-TRIFLUOROMETHYL-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

To a stirred mixture of 2-amino-3-(trifluoromethyl)benzoic acid (2.0 g,9.8 mmol) and imidazole (0.8 g, 12 mmol) in acetonitrile (20 mL), wasadded acetyl chloride (0.83 mL, 12 mmol) at room temperature. Themixture was stirred at room temperature overnight. To the mixture, wasadded 3-amino-piperidine-2,6-dione hydrogen chloride (1.6 g, 9.8 mmol),imidazole (1.5 g, 22 mmol) and triphenyl phosphite (3.1 mL, 12 mmol) andheated to reflux for 22 hours. To the mixture, was added water (60 mL).The suspension was filtered and washed with water (2×50 mL), ethylacetate (2×50 mL), sodium hydrogen carbonate (sat, 50 mL) and water (50mL) to give3-(2-methyl-4-oxo-8-trifluoromethyl-4H-quinazolin-3-yl)-piperidine-2,6-dioneas a white solid (0.32 g, 10% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 35/65 CH₃CN/0.1% H₃PO₄, 7.57 min (99.8%);mp: 351-353° C.; ¹H NMR (DMSO-d₆) δ 2.19-2.26 (m, 1H, CHH), 2.59-2.70(m, 5H, CH₃, 2CHH), 2.81-2.93 (m, 1H, CHH), 5.34 (dd, J=5, 11 Hz, 1H,NCH), 7.64 (t, J=8 Hz, 1H, Ar), 8.20 (d, J=8 Hz 1H, Ar), 8.31 (d, J=8Hz, 1H, Ar), 11.09 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 20.67, 24.05, 30.57,56.84, 121.48, 123.52 (q, J_(C-F)=274 Hz), 124.77 (q, J_(C-F)=30 Hz),125.98, 130.74, 132.29 (q, J_(C-F)=5 Hz), 144.20, 156.71, 159.68,169.28, 172.58; LCMS: MH=340; Anal Calcd for C₁₅H₁₂N₃O₃F₃+0.3H₂O+0.1CH₃CN: C, 52.34; H, 3.72; N, 12.45; F, 16.34. Found: C, 52.71; H, 3.52;N, 12.31; F, 15.99.

5.44 3-(8-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

Step 1: A mixture of 2-amino-3-methylbenzoic acid (2.1 g, 14 mmol) andCal (1.9 g, 12 mmol) in acetonitrile (25 mL) was stirred at roomtemperature for 5 hours. To the suspension, was added3-amino-piperidine-2,6-dione hydrogen chloride (2.3 g, 14 mmol),triethylamine (7.2 mL, 66 mmol) and acetic acid (8 mL, 132 mmol), andthe mixture was heated to reflux for 16 hours. To the mixture, was addedwater (75 mL) and stirred at room temperature for 2 hours. Thesuspension was filtered and washed with water (50 mL) and ethyl acetate(20 mL) to give 2-amino-N-(2,6-dioxo-piperidin-3-yl)-3-methyl-benzamideas a white solid (1.9 g, 61% yield): ¹H NMR (DMSO-d₆) δ 1.92-1.99 (m,1H, CHH), 2.06 (s, 3H, CH₃), 2.04-2.14 (m, 1H, CHH), 2.51-2.56 (m, 1H,CHH), 2.73-2.85 (m, 1H, CHH), 4.69-4.78 (m, 1H, NCH), 6.22 (brs, 2H,NH₂), 6.50 (t, J=8 Hz, 1H, Ar), 7.10 (d, J=8 Hz, 1H, Ar), 7.40 (d. J=8Hz, 1H, Ar), 8.47 (d, J=8 Hz, 1H, NH), 10.83 (s, 1H, NH); LCMS: MH=262.

Step 2: A stirred solution of2-amino-N-(2,6-dioxo-piperidin-3-yl)-3-methyl-benzamide (0.9 g, 3.4mmol) and trimethyl orthoformate (4.5 mL) and p-toluene sulfonic acid(250 mg) in acetonitrile (20 mL) was heated to reflux for 17 hours. Tothe mixture, was added water (75 mL) and stirred for 20 minutes. Thesuspension was filtered and washed with methanol (20 mL), water (20 mL)and ethyl acetate (20 mL) to give a purple solid. The solid in NMP (4mL) was heated at 80° C. for 30 minutes. To the solution, was addedwater (1 mL), and the mixture was allowed to cool to room temperature.The suspension was filtered and washed with water (30 mL) to give3-(8-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a lightpurple solid (660 mg, 72% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min. 240 nm, 30/70 CH₃CN/0.1% H₃PO₄, 3.07 min (98.6%);mp: 290-292° C.; ¹H NMR (DMSO-d₆) δ 2.11-2.19 (m, 1H, CHH), 2.56 (5, 3H,CH₃), 2.62-2.93 (m, 3H, CH₂, CHH), 5.48 (br, 1H, NCH), 7.46 (t, J=8 Hz,1H, Ar), 7.73 (d, J=8 Hz, 1H, Ar), 7.99 (d, J=8 Hz, 1H, Ar), 8.38 (s,1H, CH), 11.16 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 17.01, 22.53, 30.97,56.22, 121.36, 123.79, 126.51, 126.86, 135.03, 135.47, 136.39, 145.96,146.36, 159.97, 169.92, 172.52; LCMS: MH=272; Anal Calcd for C₁₄H₁₃N₃O₃:C, 61.99; H, 4.83; N, 15.49. Found: C, 61.70; H, 4.68; N, 15.40.

5.453-(6,7-DIMETHOXY-2-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

To a stirred mixture of 2-amino-4,5-dimethoxybenzoic acid (5.0 g, 25mmol) and imidazole (2.1 g, 30 mmol) in acetonitrile (50 mL), was addedacetyl chloride (2.2 mL, 30 mmol) at room temperature. The mixture wasstirred at room temperature overnight. To the mixture, was added3-amino-piperidine-2,6-dione hydrogen chloride (4.2 g, 25 mmol),imidazole (3.8 g, 56 mmol) and triphenyl phosphite (7.3 mL, 28 mmol) andheated to reflux for 22 hours. The suspension was filtered and washedwith acetonitrile (50 mL) and water (2×50 mL) to give a solid. The solidwas stirred in sodium hydrogen carbonate (sat, 50 mL), and water (50 mL)for 1 hour. The suspension was filtered and washed with water (2×50 mL)and ethyl acetate (30 mL) to give3-(6,7-dimethoxy-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dioneas a white solid (5.7 g, 68% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min. 240 nm, 20/80 CH₃CN/0.1% H₃PO₄, 3.26 min (99.8%);mp: 325° C. (decomp); ¹H NMR (DMSO-d₆) δ 2.15-2.19 (m, 1H, CHH),2.56-2.88 (m, 6H, CH₃, CH₂, CHH), 3.85 (s, 3H, CH₃), 3.90 (s, 3H, CH₃),5.22 (dd, J=5, 11 Hz, 1H, NCH), 7.09 (s, 1H, Ar), 7.35 (s, 1H, Ar),10.99 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 21.12, 23.21, 30.62, 55.63,55.97, 56.38, 104.98, 107.31, 113.27, 143.09, 148.40, 153.24, 154.83,159.76, 169.61, 172.64; LCMS: MH=332; Anal Calcd for C₁₆H₁₇N₃O₅: C,58.00; H, 5.17; N, 12.68. Found: C, 57.88; H, 5.06; N, 12.77.

5.46 3-(6,8-DICHLORO-2-METHYL-4-OXO-4H-QUINAZOLN-3-YL)-PIPERIDINE-2,6-DIONE

To a stirred mixture of 2-amino-3,5-dichlorobenzoic acid (5.0 g, 24mmol) and imidazole (1.9 g, 28 mmol) in acetonitrile (60 mL), was addedacetyl chloride (2.0 mL, 28 mmol) at room temperature. The mixture wasstirred at room temperature overnight. To the mixture, was added3-amino-piperidine-2,6-dione hydrogen chloride (3.9 g, 24 mmol),imidazole (3.5 g, 52 mmol) and triphenyl phosphite (6.8 mL, 26 mmol) andheated to reflux for 22 hours. The suspension was filtered and washedwith acetonitrile (30 mL), water (2×30 mL), and ethyl acetate (30 mL) togive3-(6,8-dichloro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dioneas a white solid (4.65 g, 58% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH₃CN/0.1% H₃PO₄, 4.78 min (100%);mp: 238-240° C.; ¹H NMR (DMSO-d₆) δ 2.15-2.22 (m, 1H, CHH), 2.55-2.69(m, 5H, CH, 2CHH), 2.78-2.91 (m, 1H, CHH), 5.33 (dd, J=6, 11 Hz, 1H,NCH), 7.96 (d, J=2 Hz, 1H. Ar), 8.15 (d, J=2 Hz, 1H, Ar), 11.09 (s, 1H,NH); ¹³C NMR (DMSO-d₆) δ 20.63, 23.85, 30.54, 56.92, 122.55, 24.24,130.51, 131.72, 134.38, 142.25, 156.80, 159.07, 169.12, 172.53; LCMS:MH=340, 342; Anal Calcd for C₁₄H₁₁N₃O₃Cl₂: C, 49.43; H, 3.26; N, 12.35;Cl, 20.84. Found: C, 49.21; H, 3.11; N, 12.30; Cl, 19.43.

5.47 3-(2-METHYL-4-OXO-4H-BENZO[G]QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

To a stirred mixture of 3-amino-2-naphtholic acid (5.4 g, 29 mmol) andimidazole (2 g, 29 mmol) in acetonitrile (60 mL), was added acetylchloride (2.1 mL, 29 mmol) at room temperature. The mixture was stirredat room temperature overnight. To the mixture, was added3-amino-piperidine-2,6-dione hydrogen chloride (4 g, 25 mmol), imidazole(3.7 g, 54 mmol) and triphenyl phosphite (7.1 mL, 27 mmol) and heated toreflux for 22 hours. The suspension was filtered and washed withacetonitrile (30 mL), water (2×30 mL), and ethyl acetate (30 mL) to give3-(2-methyl-4-oxo-4H-benzo[g]quinazolin-3-yl)-piperidine-2,6-dione as apale white solid (6.3 g, 79% yield): HPLC: Waters Symmetry C₁₈, 5 nm,3.9×150 mm, 1 mL/min. 240 nm, 30/70 CH₃CN/0.1% H₃PO₄, 4.59 min (99.7%);mp: 307° C. (decomp); ¹H NMR (DMSO-d₆) δ 2.17-2.26 (m, 1H, CHH),2.60-2.94 (m, 6H, CH₁, CH₂, CHH), 5.29 (dd, J=5, 11 Hz, 1H. NCH),7.55-7.60 (m, 1H, Ar), 7.64-7.69 (m, 1H, Ar), 8.09 (d, J=8 Hz, 1H, Ar),8.18-8.20 (m, 2H, Ar), 8.75 (s, 1H, Ar), 11.06 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 21.16, 23, 60, 30.71, 56.45, 119.52, 123.86, 126.25, 127.47,127.77, 128.58, 129.24, 129.53, 136.26, 142.20, 153.87, 160.97, 169.70,172.68; LCMS: MH=322; Anal Calcd for C₁₈H₁₅N₃O₃+0.1H₂O: C, 66.91; H,4.74; N, 13.00. Found: C, 66.78; H, 4.76; N, 12.95.

5.48 ASSAYS

5.48.1 TNFα Inhibition Assay in PMBC

Peripheral blood mononuclear cells (PBMC) from normal donors areobtained by Ficoll Hypaque (Pharmacia, Piscataway, N.J., USA) densitycentrifugation. Cells are cultured in RPM, 1640 (Life Technologies,Grand Island, N.Y., USA) supplemented with 10% AB+human serum (GeminiBio-products, Woodland, Calif., USA), 2 mM L-glutamine, 100 U/mlpenicillin, and 100 ng/ml streptomycin (Life Technologies).

PBMC (2×10⁵ cells) are plated in 96-well flat-bottom Costar tissueculture plates (Corning, N.Y., USA) in triplicate. Cells are stimulatedwith LPS (from Salmonella abortus equi, Sigma cat.no. L-1887, St. Louis,Mo., USA) at 1 ng/ml final in the absence or presence of compounds.Compounds provided herein are dissolved in DMSO (Sigma) and furtherdilutions are done in culture medium immediately before use. The finalDMSO concentration in all assays can be about 0.25%. Compounds are addedto cells 1 hour before LPS stimulation. Cells are then incubated for18-20 hours at 37° C. in 5% CO₂, and supernatants are then collected,diluted with culture medium and assayed for TNFα, levels by ELISA(Endogen, Boston, Mass., USA). IC₅₀s are calculated using non-linearregression, sigmoidal dose-response, constraining the top to 100% andbottom to 0%, allowing variable slope (GraphPad Prism v3.02).

5.48.2 IL-2 and MIP-3α Production by T Cells

PBMC are depleted of adherent monocytes by placing 1×10⁸ PBMC in 10 mlcomplete medium (RPMI 1640 supplemented with 10% heat-inactivated fetalbovine serum, 2 mM L-glutamine, 100 U/ml penicillin, and 100 μg/mlstreptomycin) per 10 cm tissue culture dish, in 37° C., 5% CO₂ incubatorfor 30-60 minutes. The dish is rinsed with medium to remove allnon-adherent PBMC. T cells are purified by negative selection using thefollowing antibody (Pharmingen) and Dynabead (Dynal) mixture for every1×10⁸ non-adherent PBMC: 0.3 ml Sheep anti-mouse IgG beads, 15 μlanti-CD16, 15 μl anti-CD33, 15 n1 anti-CD56, 0.23 ml anti-CD19 beads,0.23 ml anti-HLA class II beads, and 56 μl anti-CD14 beads. The cellsand bead/antibody mixture is rotated end-over-end for 30-60 minutes at4° C. Purified T cells are removed from beads using a Dynal magnet.Typical yield is about 50% T cells, 87-95% CD3⁺ by flow cytometry.

Tissue culture 96-well flat-bottom plates are coated with anti-CD3antibody OKT3 at 5 μg/ml in PBS, 100 μl per well, incubated at 37° C.for 3-6 hours, then washed four times with complete medium 100 μl/welljust before T cells are added. Compounds are diluted to 20 times offinal in a round bottom tissue culture 96-well plate. Finalconcentrations are about 10 μM to about 0.00064 μM. A 10 mM stock ofcompounds provided herein is diluted 1:50 in complete for the first 20×dilution of 200 μM in 2% DMSO and serially diluted 1:5 into 2% DMSO.Compound is added at 10 μl per 200 μl culture, to give a final DMSOconcentration of 0.1%. Cultures are incubated at 37° C., 5% CO₂ for 2-3days, and supernatants analyzed for IL-2 and MIP-3α by ELISA (R&DSystems). IL-2 and MIP-3α levels are normalized to the amount producedin the presence of an amount of a compound provided herein, and EC₅₀scalculated using non-linear regression, sigmoidal dose-response,constraining the top to 100% and bottom to 0%, allowing variable slope(GraphPad Prism v3.02).

5.48.3 Cell Proliferation Assay

Cell lines Namalwa, MUTZ-5, and UT-7 are obtained from the DeutscheSammlung von Mikroorganismen and Zellkulturen GmbH (Braunschweig,Germany). The cell line KG-1 is obtained from the American Type CultureCollection (Manassas, Va., USA). Cell proliferation as indicated by³H-thymidine incorporation is measured in all cell lines as follows.

Cells are plated in 96-well plates at 6000 cells per well in media. Thecells are pre-treated with compounds at about 100, 10, 1, 0.1, 0.01,0.001, 0.0001 and 0 μM in a final concentration of about 0.25% DMSO intriplicate at 37° C. in a humidified incubator at 5% CO₂ for 72 hours.One microcurie of ³H-thymidine (Amersham) is then added to each well,and cells are incubated again at 37° C. in a humidified incubator at 5%CO₂ for 6 hours. The cells are harvested onto UniFilter GF/C filterplates (Perkin Elmer) using a cell harvester (Tomtec), and the platesare allowed to dry overnight. Microscint 20 (Packard) (25 μl/well) isadded, and plates are analyzed in TopCount NXT (Packard). Each well iscounted for one minute. Percent inhibition of cell proliferation iscalculated by averaging all triplicates and normalizing to the DMSOcontrol (0% inhibition). Each compound is tested in each cell line inthree separate experiments. Final IC₅₀s are calculated using non-linearregression, sigmoidal dose-response, constraining the top to 100% andbottom to 0%, allowing variable slope. (GraphPad Prism v3.02).

5.48.4 Immunoprecipitation and Immunoblot

Namalwa cells are treated with DMSO or an amount of a compound providedherein for 1 hour, then stimulated with 10 U/ml of Epo (R&D Systems) for30 minutes. Cell lysates are prepared and either immunoprecipitated withEpo receptor Ab or separated immediately by SDS-PAGE. Immunoblots areprobed with Akt, phospho-Akt (Ser473 or Thr308), phospho-Gab1 (Y627),Gab1, IRS2, actin and IRF-1 Abs and analyzed on a Storm 860 Imager usingImageQuant software (Molecular Dynamics).

5.48.5 Cell Cycle Analysis

Cells are treated with DMSO or an amount of a compound provided hereinovernight. Propidium iodide staining for cell cycle is performed usingCycleTEST PLUS (Becton Dickinson) according to manufacturer's protocol.Following staining, cells are analyzed by a FACSCalibur flow cytometerusing ModFit LT software (Becton Dickinson).

5.48.6 Apoptosis Analysis

Cells are treated with DMSO or an amount of a compound provided hereinat various time points, then washed with annexin-V wash buffer (BDBiosciences). Cells are incubated with annexin-V binding protein andpropidium iodide (BD Biosciences) for 10 minutes. Samples are analyzedusing flow cytometry.

5.48.7 Luciferase Assay

Namalwa cells are transfected with 4 μg of AP1-luciferase (Stratagene)per 1×10⁶ cells and 3 μl Lipofectamine 2000 (Invitrogen) reagentaccording to manufacturer's instructions. Six hours post-transfection,cells are treated with DMSO or an amount of a compound provided herein.Luciferase activity is assayed using luciferase lysis buffer andsubstrate (Promega) and measured using a luminometer (Turner Designs).

5.48.8 Anti-Proliferation Assay

Day 1: The cells are seeded to 96-well plate with 50 ul/well in 10% FBSRPMI (w/Glutamine, w/o pen-strip) for overnight. The following cells areused:

Colorectal cancer cell: Colo 205 3200 cells/well; positive controlirinotecan

Pancreatic cancer cell: BXPC-3 1200 cells/well; positive controlgemcitabine

Prostate cancer cell: PC3 1200 cells/well; positive control docetaxel

Breast cancer cell: MDA-MB-231 2400 cells/well; positive controlpaclitaxel

Day 2: The compounds are serially diluted from 0.00001 μm˜10 μm (or0.000001˜1 μM) with 50 μl/well (of 2×) and added to the plates induplicate with relative positive control. The plates were then incubatedat 37° C. for 72 hours.

Day 5: The results are detected by CellTiter Glo method. 100 μl/well ofCellTiter Glo reagent is added to the plates and incubated for 10minutes at room temperature, and then analyzed on the Top Count reader.The IC₅₀ of each compound is typically based on the result of two ormore individually experiments.

5.49 TNFα INHIBITION

Abilities of certain compounds for inhibiting TNFα were determined usingprocedures substantially similar to those described in Section 5.48.1,above.

The tested compounds included:3-(7-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;3-(2,7-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;3-(6,7-dimethoxy-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;3-(7-fluoro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;3-(7-chloro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;3-(7-bromo-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;3-(8-bromo-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;3-(8-hydroxy-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;3-(2-methyl-4-oxo-8-trifluoromethyl-4H-quinazolin-3-yl)-piperidine-2,6-dione;heptanoic acid[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-amide;cyclopropanecarboxylic acid[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-amide;2-(4-chloro-phenyl)-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-acetamide;1-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-hexyl-urea;1-(4-chloro-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-urea;1-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-m-tolyl-urea;1-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-(4-trifluoromethoxy-phenyl)-urea;N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-4-trifluoromethyl-sulfanyl-benzamide;1-(3-chloro-4-methyl-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-urea;4-chloro-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-benzamide;N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-trifluoromethyl-benzamide;N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-4-trifluoromethoxy-benzamide;3,4-dichloro-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-benzamide:andN-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-4-trifluoromethyl-benzamide.From the tests, it was determined that IC₅₀ values of the testedcompounds were in the range of 0.01 to 25 μM.

5.50 IL-2 PRODUCTION

Abilities of certain compounds for stimulating the production of IL-2were determined using procedures substantially similar to thosedescribed in Section 5.48.2, above.

The tested compounds included:3-(6-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;3-(7-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;3-(7-fluoro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;3-(7-chloro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;3-(7-bromo-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;3-(6-hydroxy-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;1-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-hexyl-urea;and1-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-(4-trifluoromethoxy-phenyl)-urea.From the tests, it was determined that EC₅₀ values of the testedcompounds were in the range of 0.1 to 3.5 μM.

5.51 CELL PROLIFERATION

Abilities of certain compounds for inhibiting proliferation of NamalwaAG4 cells were determined using procedures substantially similar tothose described in Section 5.48.3, above.

The tested compounds included:3-(6-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine, 6-dione;3-(7-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;3-(7-fluoro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;3-(7-chloro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;3-(7-bromo-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione;heptanoic acid[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-amide;2-(4-chloro-phenyl)-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-acetamide;1-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-hexyl-urea;1-(4-chloro-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-urea;1-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-m-tolyl-urea;1-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-(4-trifluoromethoxy-phenyl)-urea;N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-4-trifluoromethyl-sulfanyl-benzamide;1-(3-chloro-4-methyl-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-urea;N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-trifluoromethyl-benzamide;N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-4-trifluoromethoxy-benzamide;3,4-dichloro-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-benzamide;andN-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-4-trifluoromethyl-benzamide.From the tests, it was determined that IC₅₀ values of the testedcompounds were in the range of 0.01 to 5.5 μM.

The embodiments of the invention described above are intended to bemerely exemplary, and those skilled in the art will recognize, or willbe able to ascertain using no more than routine experimentation,numerous equivalents of specific compounds, materials, and procedures.All such equivalents are considered to be within the scope of theinvention and are encompassed by the appended claims.

All of the patents, patent applications and publications referred toherein are incorporated herein in their entireties. Citation oridentification of any reference in this application is not an admissionthat such reference is available as prior art to this invention. Thefull scope of the invention is better understood with reference to theappended claims.

1. (canceled)
 2. A compound of formula (II):

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein: R⁷ is: hydrogen; halo; —(CH₂)_(n)OH; (C₁-C₆)alkyl, optionallysubstituted with one or more halo; (C₁-C₆)alkoxy, optionally substitutedwith one or more halo; or —(CH₂)_(n)NHR^(d), wherein R^(d) is: hydrogen;(C₁-C₆)alkyl, optionally substituted with one or more halo;—(CH₂)_(n)-(6 to 10 membered aryl); —C(O)—(CH₂)_(n)-(6 to 10 memberedaryl) or —C(O)—(CH₂)_(n)-(6 to 10 membered heteroaryl), wherein the arylor heteroaryl is optionally substituted with one or more of: halo;—SCF₃; (C₁-C₆)alkyl, itself optionally substituted with one or morehalo; or (C₁-C₆)alkoxy, itself optionally substituted with one or morehalo; —C(O)—(C₁-C₈)alkyl, wherein the alkyl is optionally substitutedwith one or more halo; —C(O)—(CH₂)_(n)—(C₃-C₁₀-cycloalkyl); —C(O)—(CH₂),—NR^(e)R^(f), wherein R^(e) and R^(f) are each independently: hydrogen;(C₁-C₆)alkyl, optionally substituted with one or more halo;(C₁-C₆)alkoxy, optionally substituted with one or more halo; or 6 to 10membered aryl, optionally substituted with one or more of: halo;(C₁-C₆)alkyl, itself optionally substituted with one or more halo; or(C₁-C₆)alkoxy, itself optionally substituted with one or more halo;—C(O)—(CH₂)—O—(C₁-C₆)alkyl; or —C(O)—(CH₂)_(n)—O—(CH₂)_(n)-(6 to 10membered aryl); R⁸ is: hydrogen; —(CH₂)_(n)OH; phenyl; —O—(C₁-C₆)alkyl;or (C₁-C₆)alkyl, optionally substituted with one or more halo; R⁹ is:hydrogen; or (C₁-C₆)alkyl, optionally substituted with one or more halo;and n is 0, 1, or
 2. 3. The compound of claim 2, having a structure offormula (III):

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein: R¹⁹ is: hydrogen; halo; —(CH₂)_(n)OH; (C₁-C₆)alkyl, optionallysubstituted with one or more halo; or (C₁-C₆)alkoxy, optionallysubstituted with one or more halo; R¹¹ is: hydrogen; —(CH₂)_(n)OH;phenyl; —O—(C₁-C₆)alkyl; or (C₁-C₆)alkyl, optionally substituted withone or more halo; R¹² is: hydrogen; or (C₁-C₆)alkyl, optionallysubstituted with one or more halo; and n is 0, 1, or
 2. 4. The compoundof claim 3, wherein R¹⁰ is a halogen, methyl, or hydroxyl.
 5. Thecompound of claim 3, wherein R¹¹ is hydrogen or methyl.
 6. The compoundof claim 3, wherein R¹² is hydrogen or methyl.
 7. The compound of claim3, which is:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.8. The compound of claim 2 having a structure of formula (IV):

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein: R^(g) is: hydrogen; (C₁-C₆)alkyl, optionally substituted withone or more halo; —(CH₂)_(n)-(6 to 10 membered aryl); —C(O)—(CH₂)_(n)-(6to 10 membered aryl) or —C(O)—(CH₂)_(n)-(6 to 10 membered heteroaryl),wherein the aryl or heteroaryl is optionally substituted with one ormore of: halo; —SCF₃; (C₁-C₆)alkyl, itself optionally substituted withone or more halo; or (C₁-C₆)alkoxy, itself optionally substituted withone or more halo; —C(O)—(C₁-C₈)alkyl, wherein the alkyl is optionallysubstituted with one or more halo; —C(O)—(CH₂)—(C₃-C₁₀-cycloalkyl);—C(O)—(CH₂), —NR^(h)R^(i), wherein R^(h) and R^(i) are eachindependently: hydrogen; (C₁-C₆)alkyl, optionally substituted with oneor more halo; (C₁-C₆)alkoxy, optionally substituted with one or morehalo; or 6 to 10 membered aryl, optionally substituted with one or moreof: halo; (C₁-C₆)alkyl, itself optionally substituted with one or morehalo; or (C₁-C₆)alkoxy, itself optionally substituted with one or morehalo; —C(O)—(CH₂)₁—O—(C₁-C₆)alkyl; or —C(O)—(CH₂)_(n)—O—(CH₂)_(n)-(6 to10 membered aryl); R¹³ is: hydrogen; —(CH₂)_(n)OH; phenyl;—O—(C₁-C₆)alkyl; or (C₁-C₆)alkyl, optionally substituted with one ormore halo; R¹⁴ is: hydrogen; or (C₁-C₆)alkyl, optionally substitutedwith one or more halo; and n is 0, 1, or
 2. 9. The compound of claim 8,wherein R^(g) is hydrogen.
 10. The compound of claim 8, wherein R^(g) is—C(O)—(C₁-C₆)alkyl.
 11. The compound of claim 8, wherein R^(g) is—C(O)-phenyl, optionally substituted with one or more of methyl, halo,and (C₁-C₆)alkyl.
 12. The compound of claim 8, which is:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.13-30. (canceled)
 31. A pharmaceutical composition comprising a compoundof claim 2, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof.